Chronic pulmonary disease continues to be a major cause of morbidity and mortality in individuals living with the human immunodeficiency virus, even with optimal HIV control. And this is independent, as seen in many studies, of age, smoking, and pulmonary infections.

Both chronic pulmonary obstructive disease (COPD) and lung cancer occur more frequently in people living with HIV than in the general population, and at earlier ages, and with worse outcomes. The risk for emphysema and interstitial lung abnormalities also appears to be higher, research has shown. And asthma has also recently emerged as another important lung disease in people with HIV (PWH).

“There is evidence that the severity of immunocompromise associated with HIV infection is linked with chronic lung diseases. People who have a lower CD4 cell count or a higher viral load do have an increased risk of COPD and emphysema as well as potentially lung cancer. But [while] immunocompromise plays a role, it isn’t the only story, given that even with well-controlled HIV there is increased risk,” said Kristina Crothers, MD, professor in the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle.

Research has evolved from a focus on the epidemiology of HIV-related chronic lung diseases to a current emphasis on “trying to understand further the mechanisms [behind the heightened risk] through more benchwork and corollary translational studies, and then to the next level of trying to understand what this means for how we should manage people with HIV who have chronic lung diseases,” Dr. Crothers said. “Should management be tailored for people with HIV infection?”

Impairments in immune pathways, local and systemic inflammation, oxidative stress, dysbiosis, and accelerated cellular senescence are among potential mechanisms, but until ongoing mechanistic research yields more answers, pulmonologists should simply – but importantly – be aware of the increased risk and have a low threshold for investigating respiratory symptoms, she and other experts said in interviews. Referral of eligible patients for lung cancer screening is also a priority, as is smoking cessation, they said.

Notably, while spirometry has been the most commonly studied lung function measure in PWH, another noninvasive measure, diffusing capacity for carbon monoxide (DLCO), has garnered attention in the past decade and thus far appears to be the more frequent lung function abnormality.

In an analysis published in 2020 from the longitudinal Multicenter AIDS Cohort Study (MACS) – a study of a subcohort of 591 men with HIV and 476 without HIV – those with HIV were found to have a 1.6-fold increased risk of mild DLCO impairment (< 80% of predicted normal) and a 3-fold higher risk of more severe DLCO impairment (< 60% of predicted normal). There was no significant difference in spirometry findings by HIV status.

Such findings on DLCO are worthy of consideration in clinical practice, even in the absence of HIV-specific screening guidelines for noncommunicable lung diseases, Dr. Crothers said. “In thinking about screening and diagnosing chronic lung diseases in these patients, I’d not only consider spirometry, but also diffusing capacity” when possible, she said. Impaired DLCO is seen with emphysema and pulmonary vascular diseases like pulmonary hypertension and also interstitial lung diseases.
 

Key chronic lung diseases

Ken M. Kunisaki, MD, MS, associate professor of medicine at the University of Minnesota, Minneapolis, and the first author of the MACS analysis of lung function – one of the most recent and largest reports of DLCO impairment – points out that studies of chest computed tomography (CT) have also documented higher rates of emphysema and interstitial lung abnormalities.

A chest CT analysis from a cohort in Denmark (the Copenhagen Comorbidity in HIV Infection [COCOMO] cohort) found interstitial lung abnormalities in 10.9% of more than 700 PWH which represented a 1.8-fold increased risk compared to HIV-negative controls. And a study from an Italian sample of never-smoking PWH and controls reported emphysema in 18% and 4%, respectively. These studies, which did not measure DLCO, are among those discussed in a 2021 review by Dr. Kunisaki of advances in HIV-associated chronic lung disease research.

COPD is the best studied and most commonly encountered chronic lung disease in PWH. “Particularly for COPD, what’s both interesting and unfortunate is that we haven’t really seen any changes in the epidemiology with ART (antiretroviral therapy) – we’re still seeing the same findings, like the association of HIV with worse COPD at younger ages,” said Alison Morris, MD, MS, professor of medicine, immunology, and clinical and translational research at the University of Pittsburgh. “It doesn’t seem to have improved.”

Its prevalence has varied widely from cohort to cohort, from as low as 3% (similar to the general population) to over 40%, Dr. Kunisaki said, emphasizing that many studies, including studies showing higher rates, have controlled for current and past smoking. In evaluating patients with low or no smoking burden, “don’t discount respiratory symptoms as possibly reflecting underlying lung disease because COPD can develop with low to no smoking history in those with HIV,” he advised.

A better understanding of how a chronic viral infection like HIV leads to heightened COPD risk will not only help those with HIV, he notes, but also people without HIV who have COPD but have never smoked – a woefully underappreciated and understudied population. Ongoing research, he said, “should help us understand COPD pathogenesis generally.”

Research on asthma is relatively limited thus far, but it does appear that PWH may be more prone to developing severe asthma, just as with COPD, said Dr. Kunisaki, also a staff physician at the Minneapolis Veterans Administration Health Care System. Research has shown, for instance, that people with HIV more frequently needed aggressive respiratory support when hospitalized for asthma exacerbations.

It’s unclear how much of this potentially increased severity is attributable to the biology of HIV’s impact on the body and how much relates to social factors like disparities in income and access to care, Dr. Kunisaki said, noting that the same questions apply to the more frequent COPD exacerbations documented in PWH.

Dr. Crothers points out that, while most studies do not suggest a difference in the incidence of asthma in PWH, “there is some data from researchers looking at asthma profiles [suggesting] that the biomarkers associated with asthma may be different in people with and without HIV,” signaling potentially different molecular or biologic underpinnings of the disease.

Incidence rates of lung cancer in PWH, meanwhile, have declined over the last 2 decades, but lung cancer remains the leading cause of cancer-related mortality in PWH and occurs at a rate that is 2-2.5 times higher than that of individuals not infected with HIV, according to

Janice Leung, MD, of the division of respiratory medicine at the University of British Columbia and the Centre for Heart Lung Innovation at St. Paul’s Hospital in Vancouver.

Patients with HIV have “worse outcomes overall and a higher risk of mortality, even when presenting at the same stage,” said Dr. Leung, who reviewed trends in COPD and lung cancer in a recently published opinion piece.
 

Potential drivers

A bird’s eye view of potential – and likely interrelated – mechanisms for chronic lung disease includes chronic immune activation that impairs innate and adaptive immune pathways; chronic inflammation systemically and in the lung despite viral suppression; persistence of the virus in latent reservoirs in the lung, particularly in alveolar macrophages and T cells; HIV-related proteins contributing to oxidative stress; accelerated cellular aging; dysbiosis; and ongoing injury from inhaled toxins.

All are described in the literature and are being further explored. “It’s likely that multiple pathways are playing a role,” said Dr. Crothers, “and it could be that the balance of one to another leads to different manifestations of disease.”

Biomarkers that have been elevated and associated with different features of chronic lung disease – such as airflow obstruction, low DLCO, and emphysema – include markers of inflammation (e.g., C-reactive protein, interleukin-6), monocyte activation (e.g., soluble CD14), and markers of endothelial dysfunction, she noted in a 2021 commentary marking 40 years since the first reported cases of acquired immunodeficiency syndrome.

In her laboratory, Dr. Leung is using new epigenetic markers to look at the pathogenesis of accelerated aging in the lung. By profiling bronchial epithelial brushings for DNA methylation and gene expression, they have found that “people living with both HIV and COPD have the fastest epigenetic age acceleration in their airway epithelium,” she said. The findings “suggest that the HIV lung is aging faster.”

They reported their findings in 2022, describing methylation disruptions along age-related pathways such as cellular senescence, longevity regulation, and insulin signaling.

Dr. Leung and her team have also studied the lung microbiome and found lower microbial diversity in the airway epithelium in patients with HIV than those without, especially in those with HIV and COPD. The National Institutes of Health–sponsored Lung HIV Microbiome Project found that changes in the lung microbiome are most pronounced in patients who haven’t yet initiated ART, but research in her lab suggests ongoing suppression of microbial diversity even after ART, she said.

Dr. Morris is particularly interested in the oral microbiome, having found through her research that changes in the oral microbiome in PWH were more related to impaired lung function than alterations in the lung and gut microbiome. “That may be in part because of the way we measure things,” she said. “But we also think that the oral microbiome probably seeds the lung [through micro-aspiration].” A study published in 2020 from the Pittsburgh site of the MACS described alterations in oral microbial communities in PWH with abnormal lung function.

Preliminary research suggests that improved dental cleaning and periodontal work in PWH and COPD may influence the severity of COPD, she noted.

“We don’t see as much of a signal with the gut microbiome [and HIV status or lung function], though there could still be ways in which gut microbiome influences the lung,” through systemic inflammation, the release of metabolites into the bloodstream, or microbial translocation, for instance, she said.

The potential role of translocation of members of the microbiome, in fact, is an area of active research for Dr. Morris. Members of the microbiome – viruses and fungi in addition to bacteria – “can get into the bloodstream from the mouth, from the lung, from the gut, to stimulate inflammation and worsen lung disease,” she said.
 

Key questions in an evolving research landscape

Dr. Kunisaki looks forward to research providing a more longitudinal look at lung function decline– a move beyond a dominance of cross-sectional studies – as well as research that is more comprehensive, with simultaneous collection of various functional measures (eg., DLCO with chest imaging and fractional excretion of nitric oxide (FENO – a standardized breath measure of Th2 airway inflammation).

The several-year-old NIH-supported MACS/WIHS (Women’s Interagency HIV Study) Combined Cohort study, in which Dr. Kunisaki and Dr. Morris participate, aims in part to identity biomarkers of increased risk for chronic lung disease and other chronic disorders and to develop strategies for more effective interventions and treatments.

Researchers will also share biospecimens, “which will allow more mechanistic work,” Dr. Kunisaki noted. (The combined cohort study includes participants from the earlier, separate MACS and WIHS studies.)

Questions about treatment strategies include the risks versus benefits of inhaled corticosteroids, which may increase an already elevated risk of respiratory infections like bacterial pneumonia in PWH, Dr. Kunisaki said.

[An aside: Inhaled corticosteroids also have well-described interactions with ART regimens that contain CYP3A4 inhibitors (e.g., ritonavir and cobicistat) that can lead to hypercortisolism. In patients who require both types of drugs, he said, beclomethasone has the least interactions and is the preferred inhaled corticosteroid.]

For Dr. Crothers, unanswered critical questions include – as she wrote in her 2021 commentary – the question of how guidelines for the management of COPD and asthma should be adapted for PWH. Is COPD in PWH more or less responsive to inhaled corticosteroids, for instance? And are antifibrotic treatments for interstitial lung disease and immunotherapies for asthma or lung cancer similarly effective, and are there any increased risks for harms in people with HIV?

There’s also the question of whether PWH should be screened for lung cancer earlier and with a lower smoking exposure than is advised under current guidelines for the general population, she said in the interview. “And should the approach to shared decision-making be modified for people with HIV?” she said. “We’re doing some work on these questions” right now.

None of the researchers interviewed reported any conflicts of interest relevant to the story. Dr. Kunisaki reported that he has no relevant disclosures, and said that his comments are his personal views and not official views of the U.S. Government, Department of Veterans Affairs, the Minneapolis VA, or the University of Minnesota.

Chronic pulmonary disease continues to be a major cause of morbidity and mortality in individuals living with the human immunodeficiency virus, even with optimal HIV control. And this is independent, as seen in many studies, of age, smoking, and pulmonary infections.

Both chronic pulmonary obstructive disease (COPD) and lung cancer occur more frequently in people living with HIV than in the general population, and at earlier ages, and with worse outcomes. The risk for emphysema and interstitial lung abnormalities also appears to be higher, research has shown. And asthma has also recently emerged as another important lung disease in people with HIV (PWH).

“There is evidence that the severity of immunocompromise associated with HIV infection is linked with chronic lung diseases. People who have a lower CD4 cell count or a higher viral load do have an increased risk of COPD and emphysema as well as potentially lung cancer. But [while] immunocompromise plays a role, it isn’t the only story, given that even with well-controlled HIV there is increased risk,” said Kristina Crothers, MD, professor in the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle.

Research has evolved from a focus on the epidemiology of HIV-related chronic lung diseases to a current emphasis on “trying to understand further the mechanisms [behind the heightened risk] through more benchwork and corollary translational studies, and then to the next level of trying to understand what this means for how we should manage people with HIV who have chronic lung diseases,” Dr. Crothers said. “Should management be tailored for people with HIV infection?”

Impairments in immune pathways, local and systemic inflammation, oxidative stress, dysbiosis, and accelerated cellular senescence are among potential mechanisms, but until ongoing mechanistic research yields more answers, pulmonologists should simply – but importantly – be aware of the increased risk and have a low threshold for investigating respiratory symptoms, she and other experts said in interviews. Referral of eligible patients for lung cancer screening is also a priority, as is smoking cessation, they said.

Notably, while spirometry has been the most commonly studied lung function measure in PWH, another noninvasive measure, diffusing capacity for carbon monoxide (DLCO), has garnered attention in the past decade and thus far appears to be the more frequent lung function abnormality.

In an analysis published in 2020 from the longitudinal Multicenter AIDS Cohort Study (MACS) – a study of a subcohort of 591 men with HIV and 476 without HIV – those with HIV were found to have a 1.6-fold increased risk of mild DLCO impairment (< 80% of predicted normal) and a 3-fold higher risk of more severe DLCO impairment (< 60% of predicted normal). There was no significant difference in spirometry findings by HIV status.

Such findings on DLCO are worthy of consideration in clinical practice, even in the absence of HIV-specific screening guidelines for noncommunicable lung diseases, Dr. Crothers said. “In thinking about screening and diagnosing chronic lung diseases in these patients, I’d not only consider spirometry, but also diffusing capacity” when possible, she said. Impaired DLCO is seen with emphysema and pulmonary vascular diseases like pulmonary hypertension and also interstitial lung diseases.
 

Key chronic lung diseases

Ken M. Kunisaki, MD, MS, associate professor of medicine at the University of Minnesota, Minneapolis, and the first author of the MACS analysis of lung function – one of the most recent and largest reports of DLCO impairment – points out that studies of chest computed tomography (CT) have also documented higher rates of emphysema and interstitial lung abnormalities.

A chest CT analysis from a cohort in Denmark (the Copenhagen Comorbidity in HIV Infection [COCOMO] cohort) found interstitial lung abnormalities in 10.9% of more than 700 PWH which represented a 1.8-fold increased risk compared to HIV-negative controls. And a study from an Italian sample of never-smoking PWH and controls reported emphysema in 18% and 4%, respectively. These studies, which did not measure DLCO, are among those discussed in a 2021 review by Dr. Kunisaki of advances in HIV-associated chronic lung disease research.

COPD is the best studied and most commonly encountered chronic lung disease in PWH. “Particularly for COPD, what’s both interesting and unfortunate is that we haven’t really seen any changes in the epidemiology with ART (antiretroviral therapy) – we’re still seeing the same findings, like the association of HIV with worse COPD at younger ages,” said Alison Morris, MD, MS, professor of medicine, immunology, and clinical and translational research at the University of Pittsburgh. “It doesn’t seem to have improved.”

Its prevalence has varied widely from cohort to cohort, from as low as 3% (similar to the general population) to over 40%, Dr. Kunisaki said, emphasizing that many studies, including studies showing higher rates, have controlled for current and past smoking. In evaluating patients with low or no smoking burden, “don’t discount respiratory symptoms as possibly reflecting underlying lung disease because COPD can develop with low to no smoking history in those with HIV,” he advised.

A better understanding of how a chronic viral infection like HIV leads to heightened COPD risk will not only help those with HIV, he notes, but also people without HIV who have COPD but have never smoked – a woefully underappreciated and understudied population. Ongoing research, he said, “should help us understand COPD pathogenesis generally.”

Research on asthma is relatively limited thus far, but it does appear that PWH may be more prone to developing severe asthma, just as with COPD, said Dr. Kunisaki, also a staff physician at the Minneapolis Veterans Administration Health Care System. Research has shown, for instance, that people with HIV more frequently needed aggressive respiratory support when hospitalized for asthma exacerbations.

It’s unclear how much of this potentially increased severity is attributable to the biology of HIV’s impact on the body and how much relates to social factors like disparities in income and access to care, Dr. Kunisaki said, noting that the same questions apply to the more frequent COPD exacerbations documented in PWH.

Dr. Crothers points out that, while most studies do not suggest a difference in the incidence of asthma in PWH, “there is some data from researchers looking at asthma profiles [suggesting] that the biomarkers associated with asthma may be different in people with and without HIV,” signaling potentially different molecular or biologic underpinnings of the disease.

Incidence rates of lung cancer in PWH, meanwhile, have declined over the last 2 decades, but lung cancer remains the leading cause of cancer-related mortality in PWH and occurs at a rate that is 2-2.5 times higher than that of individuals not infected with HIV, according to

Janice Leung, MD, of the division of respiratory medicine at the University of British Columbia and the Centre for Heart Lung Innovation at St. Paul’s Hospital in Vancouver.

Patients with HIV have “worse outcomes overall and a higher risk of mortality, even when presenting at the same stage,” said Dr. Leung, who reviewed trends in COPD and lung cancer in a recently published opinion piece.
 

Potential drivers

A bird’s eye view of potential – and likely interrelated – mechanisms for chronic lung disease includes chronic immune activation that impairs innate and adaptive immune pathways; chronic inflammation systemically and in the lung despite viral suppression; persistence of the virus in latent reservoirs in the lung, particularly in alveolar macrophages and T cells; HIV-related proteins contributing to oxidative stress; accelerated cellular aging; dysbiosis; and ongoing injury from inhaled toxins.

All are described in the literature and are being further explored. “It’s likely that multiple pathways are playing a role,” said Dr. Crothers, “and it could be that the balance of one to another leads to different manifestations of disease.”

Biomarkers that have been elevated and associated with different features of chronic lung disease – such as airflow obstruction, low DLCO, and emphysema – include markers of inflammation (e.g., C-reactive protein, interleukin-6), monocyte activation (e.g., soluble CD14), and markers of endothelial dysfunction, she noted in a 2021 commentary marking 40 years since the first reported cases of acquired immunodeficiency syndrome.

In her laboratory, Dr. Leung is using new epigenetic markers to look at the pathogenesis of accelerated aging in the lung. By profiling bronchial epithelial brushings for DNA methylation and gene expression, they have found that “people living with both HIV and COPD have the fastest epigenetic age acceleration in their airway epithelium,” she said. The findings “suggest that the HIV lung is aging faster.”

They reported their findings in 2022, describing methylation disruptions along age-related pathways such as cellular senescence, longevity regulation, and insulin signaling.

Dr. Leung and her team have also studied the lung microbiome and found lower microbial diversity in the airway epithelium in patients with HIV than those without, especially in those with HIV and COPD. The National Institutes of Health–sponsored Lung HIV Microbiome Project found that changes in the lung microbiome are most pronounced in patients who haven’t yet initiated ART, but research in her lab suggests ongoing suppression of microbial diversity even after ART, she said.

Dr. Morris is particularly interested in the oral microbiome, having found through her research that changes in the oral microbiome in PWH were more related to impaired lung function than alterations in the lung and gut microbiome. “That may be in part because of the way we measure things,” she said. “But we also think that the oral microbiome probably seeds the lung [through micro-aspiration].” A study published in 2020 from the Pittsburgh site of the MACS described alterations in oral microbial communities in PWH with abnormal lung function.

Preliminary research suggests that improved dental cleaning and periodontal work in PWH and COPD may influence the severity of COPD, she noted.

“We don’t see as much of a signal with the gut microbiome [and HIV status or lung function], though there could still be ways in which gut microbiome influences the lung,” through systemic inflammation, the release of metabolites into the bloodstream, or microbial translocation, for instance, she said.

The potential role of translocation of members of the microbiome, in fact, is an area of active research for Dr. Morris. Members of the microbiome – viruses and fungi in addition to bacteria – “can get into the bloodstream from the mouth, from the lung, from the gut, to stimulate inflammation and worsen lung disease,” she said.
 

Key questions in an evolving research landscape

Dr. Kunisaki looks forward to research providing a more longitudinal look at lung function decline– a move beyond a dominance of cross-sectional studies – as well as research that is more comprehensive, with simultaneous collection of various functional measures (eg., DLCO with chest imaging and fractional excretion of nitric oxide (FENO – a standardized breath measure of Th2 airway inflammation).

The several-year-old NIH-supported MACS/WIHS (Women’s Interagency HIV Study) Combined Cohort study, in which Dr. Kunisaki and Dr. Morris participate, aims in part to identity biomarkers of increased risk for chronic lung disease and other chronic disorders and to develop strategies for more effective interventions and treatments.

Researchers will also share biospecimens, “which will allow more mechanistic work,” Dr. Kunisaki noted. (The combined cohort study includes participants from the earlier, separate MACS and WIHS studies.)

Questions about treatment strategies include the risks versus benefits of inhaled corticosteroids, which may increase an already elevated risk of respiratory infections like bacterial pneumonia in PWH, Dr. Kunisaki said.

[An aside: Inhaled corticosteroids also have well-described interactions with ART regimens that contain CYP3A4 inhibitors (e.g., ritonavir and cobicistat) that can lead to hypercortisolism. In patients who require both types of drugs, he said, beclomethasone has the least interactions and is the preferred inhaled corticosteroid.]

For Dr. Crothers, unanswered critical questions include – as she wrote in her 2021 commentary – the question of how guidelines for the management of COPD and asthma should be adapted for PWH. Is COPD in PWH more or less responsive to inhaled corticosteroids, for instance? And are antifibrotic treatments for interstitial lung disease and immunotherapies for asthma or lung cancer similarly effective, and are there any increased risks for harms in people with HIV?

There’s also the question of whether PWH should be screened for lung cancer earlier and with a lower smoking exposure than is advised under current guidelines for the general population, she said in the interview. “And should the approach to shared decision-making be modified for people with HIV?” she said. “We’re doing some work on these questions” right now.

None of the researchers interviewed reported any conflicts of interest relevant to the story. Dr. Kunisaki reported that he has no relevant disclosures, and said that his comments are his personal views and not official views of the U.S. Government, Department of Veterans Affairs, the Minneapolis VA, or the University of Minnesota.

Chronic pulmonary disease continues to be a major cause of morbidity and mortality in individuals living with the human immunodeficiency virus, even with optimal HIV control. And this is independent, as seen in many studies, of age, smoking, and pulmonary infections.

Both chronic pulmonary obstructive disease (COPD) and lung cancer occur more frequently in people living with HIV than in the general population, and at earlier ages, and with worse outcomes. The risk for emphysema and interstitial lung abnormalities also appears to be higher, research has shown. And asthma has also recently emerged as another important lung disease in people with HIV (PWH).

“There is evidence that the severity of immunocompromise associated with HIV infection is linked with chronic lung diseases. People who have a lower CD4 cell count or a higher viral load do have an increased risk of COPD and emphysema as well as potentially lung cancer. But [while] immunocompromise plays a role, it isn’t the only story, given that even with well-controlled HIV there is increased risk,” said Kristina Crothers, MD, professor in the division of pulmonary, critical care, and sleep medicine at the University of Washington, Seattle.

Research has evolved from a focus on the epidemiology of HIV-related chronic lung diseases to a current emphasis on “trying to understand further the mechanisms [behind the heightened risk] through more benchwork and corollary translational studies, and then to the next level of trying to understand what this means for how we should manage people with HIV who have chronic lung diseases,” Dr. Crothers said. “Should management be tailored for people with HIV infection?”

Impairments in immune pathways, local and systemic inflammation, oxidative stress, dysbiosis, and accelerated cellular senescence are among potential mechanisms, but until ongoing mechanistic research yields more answers, pulmonologists should simply – but importantly – be aware of the increased risk and have a low threshold for investigating respiratory symptoms, she and other experts said in interviews. Referral of eligible patients for lung cancer screening is also a priority, as is smoking cessation, they said.

Notably, while spirometry has been the most commonly studied lung function measure in PWH, another noninvasive measure, diffusing capacity for carbon monoxide (DLCO), has garnered attention in the past decade and thus far appears to be the more frequent lung function abnormality.

In an analysis published in 2020 from the longitudinal Multicenter AIDS Cohort Study (MACS) – a study of a subcohort of 591 men with HIV and 476 without HIV – those with HIV were found to have a 1.6-fold increased risk of mild DLCO impairment (< 80% of predicted normal) and a 3-fold higher risk of more severe DLCO impairment (< 60% of predicted normal). There was no significant difference in spirometry findings by HIV status.

Such findings on DLCO are worthy of consideration in clinical practice, even in the absence of HIV-specific screening guidelines for noncommunicable lung diseases, Dr. Crothers said. “In thinking about screening and diagnosing chronic lung diseases in these patients, I’d not only consider spirometry, but also diffusing capacity” when possible, she said. Impaired DLCO is seen with emphysema and pulmonary vascular diseases like pulmonary hypertension and also interstitial lung diseases.
 

Key chronic lung diseases

Ken M. Kunisaki, MD, MS, associate professor of medicine at the University of Minnesota, Minneapolis, and the first author of the MACS analysis of lung function – one of the most recent and largest reports of DLCO impairment – points out that studies of chest computed tomography (CT) have also documented higher rates of emphysema and interstitial lung abnormalities.

A chest CT analysis from a cohort in Denmark (the Copenhagen Comorbidity in HIV Infection [COCOMO] cohort) found interstitial lung abnormalities in 10.9% of more than 700 PWH which represented a 1.8-fold increased risk compared to HIV-negative controls. And a study from an Italian sample of never-smoking PWH and controls reported emphysema in 18% and 4%, respectively. These studies, which did not measure DLCO, are among those discussed in a 2021 review by Dr. Kunisaki of advances in HIV-associated chronic lung disease research.

COPD is the best studied and most commonly encountered chronic lung disease in PWH. “Particularly for COPD, what’s both interesting and unfortunate is that we haven’t really seen any changes in the epidemiology with ART (antiretroviral therapy) – we’re still seeing the same findings, like the association of HIV with worse COPD at younger ages,” said Alison Morris, MD, MS, professor of medicine, immunology, and clinical and translational research at the University of Pittsburgh. “It doesn’t seem to have improved.”

Its prevalence has varied widely from cohort to cohort, from as low as 3% (similar to the general population) to over 40%, Dr. Kunisaki said, emphasizing that many studies, including studies showing higher rates, have controlled for current and past smoking. In evaluating patients with low or no smoking burden, “don’t discount respiratory symptoms as possibly reflecting underlying lung disease because COPD can develop with low to no smoking history in those with HIV,” he advised.

A better understanding of how a chronic viral infection like HIV leads to heightened COPD risk will not only help those with HIV, he notes, but also people without HIV who have COPD but have never smoked – a woefully underappreciated and understudied population. Ongoing research, he said, “should help us understand COPD pathogenesis generally.”

Research on asthma is relatively limited thus far, but it does appear that PWH may be more prone to developing severe asthma, just as with COPD, said Dr. Kunisaki, also a staff physician at the Minneapolis Veterans Administration Health Care System. Research has shown, for instance, that people with HIV more frequently needed aggressive respiratory support when hospitalized for asthma exacerbations.

It’s unclear how much of this potentially increased severity is attributable to the biology of HIV’s impact on the body and how much relates to social factors like disparities in income and access to care, Dr. Kunisaki said, noting that the same questions apply to the more frequent COPD exacerbations documented in PWH.

Dr. Crothers points out that, while most studies do not suggest a difference in the incidence of asthma in PWH, “there is some data from researchers looking at asthma profiles [suggesting] that the biomarkers associated with asthma may be different in people with and without HIV,” signaling potentially different molecular or biologic underpinnings of the disease.

Incidence rates of lung cancer in PWH, meanwhile, have declined over the last 2 decades, but lung cancer remains the leading cause of cancer-related mortality in PWH and occurs at a rate that is 2-2.5 times higher than that of individuals not infected with HIV, according to

Janice Leung, MD, of the division of respiratory medicine at the University of British Columbia and the Centre for Heart Lung Innovation at St. Paul’s Hospital in Vancouver.

Patients with HIV have “worse outcomes overall and a higher risk of mortality, even when presenting at the same stage,” said Dr. Leung, who reviewed trends in COPD and lung cancer in a recently published opinion piece.
 

Potential drivers

A bird’s eye view of potential – and likely interrelated – mechanisms for chronic lung disease includes chronic immune activation that impairs innate and adaptive immune pathways; chronic inflammation systemically and in the lung despite viral suppression; persistence of the virus in latent reservoirs in the lung, particularly in alveolar macrophages and T cells; HIV-related proteins contributing to oxidative stress; accelerated cellular aging; dysbiosis; and ongoing injury from inhaled toxins.

All are described in the literature and are being further explored. “It’s likely that multiple pathways are playing a role,” said Dr. Crothers, “and it could be that the balance of one to another leads to different manifestations of disease.”

Biomarkers that have been elevated and associated with different features of chronic lung disease – such as airflow obstruction, low DLCO, and emphysema – include markers of inflammation (e.g., C-reactive protein, interleukin-6), monocyte activation (e.g., soluble CD14), and markers of endothelial dysfunction, she noted in a 2021 commentary marking 40 years since the first reported cases of acquired immunodeficiency syndrome.

In her laboratory, Dr. Leung is using new epigenetic markers to look at the pathogenesis of accelerated aging in the lung. By profiling bronchial epithelial brushings for DNA methylation and gene expression, they have found that “people living with both HIV and COPD have the fastest epigenetic age acceleration in their airway epithelium,” she said. The findings “suggest that the HIV lung is aging faster.”

They reported their findings in 2022, describing methylation disruptions along age-related pathways such as cellular senescence, longevity regulation, and insulin signaling.

Dr. Leung and her team have also studied the lung microbiome and found lower microbial diversity in the airway epithelium in patients with HIV than those without, especially in those with HIV and COPD. The National Institutes of Health–sponsored Lung HIV Microbiome Project found that changes in the lung microbiome are most pronounced in patients who haven’t yet initiated ART, but research in her lab suggests ongoing suppression of microbial diversity even after ART, she said.

Dr. Morris is particularly interested in the oral microbiome, having found through her research that changes in the oral microbiome in PWH were more related to impaired lung function than alterations in the lung and gut microbiome. “That may be in part because of the way we measure things,” she said. “But we also think that the oral microbiome probably seeds the lung [through micro-aspiration].” A study published in 2020 from the Pittsburgh site of the MACS described alterations in oral microbial communities in PWH with abnormal lung function.

Preliminary research suggests that improved dental cleaning and periodontal work in PWH and COPD may influence the severity of COPD, she noted.

“We don’t see as much of a signal with the gut microbiome [and HIV status or lung function], though there could still be ways in which gut microbiome influences the lung,” through systemic inflammation, the release of metabolites into the bloodstream, or microbial translocation, for instance, she said.

The potential role of translocation of members of the microbiome, in fact, is an area of active research for Dr. Morris. Members of the microbiome – viruses and fungi in addition to bacteria – “can get into the bloodstream from the mouth, from the lung, from the gut, to stimulate inflammation and worsen lung disease,” she said.
 

Key questions in an evolving research landscape

Dr. Kunisaki looks forward to research providing a more longitudinal look at lung function decline– a move beyond a dominance of cross-sectional studies – as well as research that is more comprehensive, with simultaneous collection of various functional measures (eg., DLCO with chest imaging and fractional excretion of nitric oxide (FENO – a standardized breath measure of Th2 airway inflammation).

The several-year-old NIH-supported MACS/WIHS (Women’s Interagency HIV Study) Combined Cohort study, in which Dr. Kunisaki and Dr. Morris participate, aims in part to identity biomarkers of increased risk for chronic lung disease and other chronic disorders and to develop strategies for more effective interventions and treatments.

Researchers will also share biospecimens, “which will allow more mechanistic work,” Dr. Kunisaki noted. (The combined cohort study includes participants from the earlier, separate MACS and WIHS studies.)

Questions about treatment strategies include the risks versus benefits of inhaled corticosteroids, which may increase an already elevated risk of respiratory infections like bacterial pneumonia in PWH, Dr. Kunisaki said.

[An aside: Inhaled corticosteroids also have well-described interactions with ART regimens that contain CYP3A4 inhibitors (e.g., ritonavir and cobicistat) that can lead to hypercortisolism. In patients who require both types of drugs, he said, beclomethasone has the least interactions and is the preferred inhaled corticosteroid.]

For Dr. Crothers, unanswered critical questions include – as she wrote in her 2021 commentary – the question of how guidelines for the management of COPD and asthma should be adapted for PWH. Is COPD in PWH more or less responsive to inhaled corticosteroids, for instance? And are antifibrotic treatments for interstitial lung disease and immunotherapies for asthma or lung cancer similarly effective, and are there any increased risks for harms in people with HIV?

There’s also the question of whether PWH should be screened for lung cancer earlier and with a lower smoking exposure than is advised under current guidelines for the general population, she said in the interview. “And should the approach to shared decision-making be modified for people with HIV?” she said. “We’re doing some work on these questions” right now.

None of the researchers interviewed reported any conflicts of interest relevant to the story. Dr. Kunisaki reported that he has no relevant disclosures, and said that his comments are his personal views and not official views of the U.S. Government, Department of Veterans Affairs, the Minneapolis VA, or the University of Minnesota.

In patients with fibrotic interstitial lung disease, nocturnal hypoxemia is associated with poor clinical outcomes, according to results of a prospective observational cohort study. Obstructive sleep apnea in the absence of nocturnal hypoxemia was not independently associated with poor clinical outcomes.

While both obstructive sleep apnea (OSA) and nocturnal hypoxemia (NH) are known to be common in patients with fibrotic interstitial lung disease (F-ILD), how they affect disease outcomes has remained unclear, Katherine J. Myall, MBChB, and colleagues reported in their published study. They noted that deposition of extracellular matrix within the lung parenchyma found in F-ILD is associated with restrictive lung disease and impaired gas exchange leading to progressive breathlessness and exercise intolerance and ultimately respiratory failure.

Prior research has suggested that sleep architecture is disrupted in F-ILD, with nocturnal desaturations from relative hypoventilation during rapid-eye movement sleep and higher incidence of OSA. While disrupted sleep architecture has been associated with poorer outcomes including worse survival, the relationship between sleep and F-ILD is not well understood, especially whether either total time spent in sleep with hypoxemia or repeated desaturations and arousals seen in OSA might promote disease progression, the researchers wrote.

They conducted a prospective observational cohort study among 102 idiopathic pulmonary fibrosis patients without daytime hypoxemia (74.5% male; age 73.0 years), among whom 91.1% and 31.4% had nocturnal hypoxemia (NH) and obstructive sleep apnea (OSA), respectively. There were no significant differences between those with and without NH or OSA at baseline. The study’s primary outcome measure was change in King’s Brief Interstitial Lung Disease questionnaire (KBILD) at 12 months from baseline. The secondary outcome measures were annualized change in forced vital capacity (FVC), transfer factor for carbon monoxide (TLCO), and mortality at 12 months.
 

Mortality association?

The analysis showed NH was associated with a more rapid decline in both quality of life (KBILD change –11.3 in the NH group vs. –6.7 in those without NH, P = .005) and higher all-cause mortality at 1 year (hazard ratio [HR], 8.21; 95% confidence interval [CI], 2.40-28.1, P < .001). There was no increased risk of death in patients with OSA compared with those without (HR, 2.78; 95% CI 0.85-9.12, P = .19), and OSA in the absence of NH was not associated with worsening of KBILD scores (P = .30). Analysis of findings did not reveal any relationship between disease severity and sleep characteristics.

“This suggests that the excess mortality demonstrated in earlier studies of patients with OSA may be related to prolonged hypoxemia rather than sleep disruption or the other deleterious physiological effects of OSA, such as sympathetic excitation,” noted Dr. Myall and colleagues. Underscoring that the current study is the first to elucidate the contribution of prolonged NH to disease progression and death in this population, they added that since the central process in the development of idiopathic pulmonary fibrosis is thought to be one of repeated or sustained lung injury, one hypothesis is that prolonged hypoxia of the alveolar epithelium due to prolonged nocturnal hypoxemia may be the source of this insult.

“These data provide support for screening for nocturnal hypoxemia, as well as obstructive sleep apnea in patients with F-ILD to allow early identification of these potentially modifiable conditions. Trials of CPAP and nocturnal oxygen therapy would offer a potential intervention to correct prolonged nocturnal hypoxemia, offering the potential to improve quality of life and survival for patients who otherwise have limited treatment options,” the researchers concluded.

A possible limitations of the study was the fact that patients were offered referral for CPAP therapy, and were used in the analysis only if they elected not to commence therapy. This may have introduced a bias, although there was no statistically significant difference between patients who opted to be referred and those who did not, according to the authors.

Dr. Myall reported having no conflicts of interest to declare.

In patients with fibrotic interstitial lung disease, nocturnal hypoxemia is associated with poor clinical outcomes, according to results of a prospective observational cohort study. Obstructive sleep apnea in the absence of nocturnal hypoxemia was not independently associated with poor clinical outcomes.

While both obstructive sleep apnea (OSA) and nocturnal hypoxemia (NH) are known to be common in patients with fibrotic interstitial lung disease (F-ILD), how they affect disease outcomes has remained unclear, Katherine J. Myall, MBChB, and colleagues reported in their published study. They noted that deposition of extracellular matrix within the lung parenchyma found in F-ILD is associated with restrictive lung disease and impaired gas exchange leading to progressive breathlessness and exercise intolerance and ultimately respiratory failure.

Prior research has suggested that sleep architecture is disrupted in F-ILD, with nocturnal desaturations from relative hypoventilation during rapid-eye movement sleep and higher incidence of OSA. While disrupted sleep architecture has been associated with poorer outcomes including worse survival, the relationship between sleep and F-ILD is not well understood, especially whether either total time spent in sleep with hypoxemia or repeated desaturations and arousals seen in OSA might promote disease progression, the researchers wrote.

They conducted a prospective observational cohort study among 102 idiopathic pulmonary fibrosis patients without daytime hypoxemia (74.5% male; age 73.0 years), among whom 91.1% and 31.4% had nocturnal hypoxemia (NH) and obstructive sleep apnea (OSA), respectively. There were no significant differences between those with and without NH or OSA at baseline. The study’s primary outcome measure was change in King’s Brief Interstitial Lung Disease questionnaire (KBILD) at 12 months from baseline. The secondary outcome measures were annualized change in forced vital capacity (FVC), transfer factor for carbon monoxide (TLCO), and mortality at 12 months.
 

Mortality association?

The analysis showed NH was associated with a more rapid decline in both quality of life (KBILD change –11.3 in the NH group vs. –6.7 in those without NH, P = .005) and higher all-cause mortality at 1 year (hazard ratio [HR], 8.21; 95% confidence interval [CI], 2.40-28.1, P < .001). There was no increased risk of death in patients with OSA compared with those without (HR, 2.78; 95% CI 0.85-9.12, P = .19), and OSA in the absence of NH was not associated with worsening of KBILD scores (P = .30). Analysis of findings did not reveal any relationship between disease severity and sleep characteristics.

“This suggests that the excess mortality demonstrated in earlier studies of patients with OSA may be related to prolonged hypoxemia rather than sleep disruption or the other deleterious physiological effects of OSA, such as sympathetic excitation,” noted Dr. Myall and colleagues. Underscoring that the current study is the first to elucidate the contribution of prolonged NH to disease progression and death in this population, they added that since the central process in the development of idiopathic pulmonary fibrosis is thought to be one of repeated or sustained lung injury, one hypothesis is that prolonged hypoxia of the alveolar epithelium due to prolonged nocturnal hypoxemia may be the source of this insult.

“These data provide support for screening for nocturnal hypoxemia, as well as obstructive sleep apnea in patients with F-ILD to allow early identification of these potentially modifiable conditions. Trials of CPAP and nocturnal oxygen therapy would offer a potential intervention to correct prolonged nocturnal hypoxemia, offering the potential to improve quality of life and survival for patients who otherwise have limited treatment options,” the researchers concluded.

A possible limitations of the study was the fact that patients were offered referral for CPAP therapy, and were used in the analysis only if they elected not to commence therapy. This may have introduced a bias, although there was no statistically significant difference between patients who opted to be referred and those who did not, according to the authors.

Dr. Myall reported having no conflicts of interest to declare.

In patients with fibrotic interstitial lung disease, nocturnal hypoxemia is associated with poor clinical outcomes, according to results of a prospective observational cohort study. Obstructive sleep apnea in the absence of nocturnal hypoxemia was not independently associated with poor clinical outcomes.

While both obstructive sleep apnea (OSA) and nocturnal hypoxemia (NH) are known to be common in patients with fibrotic interstitial lung disease (F-ILD), how they affect disease outcomes has remained unclear, Katherine J. Myall, MBChB, and colleagues reported in their published study. They noted that deposition of extracellular matrix within the lung parenchyma found in F-ILD is associated with restrictive lung disease and impaired gas exchange leading to progressive breathlessness and exercise intolerance and ultimately respiratory failure.

Prior research has suggested that sleep architecture is disrupted in F-ILD, with nocturnal desaturations from relative hypoventilation during rapid-eye movement sleep and higher incidence of OSA. While disrupted sleep architecture has been associated with poorer outcomes including worse survival, the relationship between sleep and F-ILD is not well understood, especially whether either total time spent in sleep with hypoxemia or repeated desaturations and arousals seen in OSA might promote disease progression, the researchers wrote.

They conducted a prospective observational cohort study among 102 idiopathic pulmonary fibrosis patients without daytime hypoxemia (74.5% male; age 73.0 years), among whom 91.1% and 31.4% had nocturnal hypoxemia (NH) and obstructive sleep apnea (OSA), respectively. There were no significant differences between those with and without NH or OSA at baseline. The study’s primary outcome measure was change in King’s Brief Interstitial Lung Disease questionnaire (KBILD) at 12 months from baseline. The secondary outcome measures were annualized change in forced vital capacity (FVC), transfer factor for carbon monoxide (TLCO), and mortality at 12 months.
 

Mortality association?

The analysis showed NH was associated with a more rapid decline in both quality of life (KBILD change –11.3 in the NH group vs. –6.7 in those without NH, P = .005) and higher all-cause mortality at 1 year (hazard ratio [HR], 8.21; 95% confidence interval [CI], 2.40-28.1, P < .001). There was no increased risk of death in patients with OSA compared with those without (HR, 2.78; 95% CI 0.85-9.12, P = .19), and OSA in the absence of NH was not associated with worsening of KBILD scores (P = .30). Analysis of findings did not reveal any relationship between disease severity and sleep characteristics.

“This suggests that the excess mortality demonstrated in earlier studies of patients with OSA may be related to prolonged hypoxemia rather than sleep disruption or the other deleterious physiological effects of OSA, such as sympathetic excitation,” noted Dr. Myall and colleagues. Underscoring that the current study is the first to elucidate the contribution of prolonged NH to disease progression and death in this population, they added that since the central process in the development of idiopathic pulmonary fibrosis is thought to be one of repeated or sustained lung injury, one hypothesis is that prolonged hypoxia of the alveolar epithelium due to prolonged nocturnal hypoxemia may be the source of this insult.

“These data provide support for screening for nocturnal hypoxemia, as well as obstructive sleep apnea in patients with F-ILD to allow early identification of these potentially modifiable conditions. Trials of CPAP and nocturnal oxygen therapy would offer a potential intervention to correct prolonged nocturnal hypoxemia, offering the potential to improve quality of life and survival for patients who otherwise have limited treatment options,” the researchers concluded.

A possible limitations of the study was the fact that patients were offered referral for CPAP therapy, and were used in the analysis only if they elected not to commence therapy. This may have introduced a bias, although there was no statistically significant difference between patients who opted to be referred and those who did not, according to the authors.

Dr. Myall reported having no conflicts of interest to declare.

The U.K. Mini Mitral trial, showing that mitral valve repair with the less invasive minithoracotomy approach achieved similar outcomes, compared with sternotomy, has now been published.

The trial, which was first presented earlier this year at the American College of Cardiology meeting, showed that minimally invasive mitral valve repair does not improve physical function at 12 weeks, compared with sternotomy, but outcomes at 1 year show minimally invasive repair is as safe and effective as sternotomy for degenerative mitral regurgitation.

The full results are now published online in JAMA.

The authors, led by Enoch Akowuah, MD, South Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom, explain that mitral valve repair surgery is the preferred treatment for patients with degenerative mitral regurgitation and is routinely performed via full sternotomy, enabling easy access to the heart, flexibility in myocardial protection strategies, and multiple ways of accessing the mitral valve and easing de-airing to prevent air emboli, which cause cerebrovascular accidents. 

However, the invasiveness of sternotomy is associated with delayed return to presurgery physical function levels and an increase in postoperative complications.

An alternative new video-guided minimally invasive approach involving a 4- to 7-cm lateral thoracotomy, completely avoiding sternotomy, has been developed, with the hope that it should speed physical recovery function after surgery and reduce postoperative complications and costs by reducing hospital stay.

Dr. Akowuah et al. note that uptake of minithoracotomy is variable, with low rates in the United States and the United Kingdom but high rates in Germany. They say that this variation is attributable to the absence of high-quality evidence from randomized trials demonstrating equivalent or superior benefits, compared with sternotomy, and there are also concerns that the increased technical complexity of minithoracotomy may impair the ability to repair complex valve lesions or increase perioperative complications, particularly vascular injuries and stroke.

The U.K. Mini Mitral trial was therefore conducted to compare the effectiveness and safety of minithoracotomy versus sternotomy mitral valve repair.

For the trial, 330 patients with degenerative mitral regurgitation were randomized to receive either minithoracotomy or sternotomy mitral valve repair performed by an expert surgeon.

The primary outcome was physical functioning and associated return to usual activities measured by change from baseline in the 36-Item Short Form Health Survey (SF-36) physical functioning scale 12 weeks after the surgery.  

This failed to show superiority of minithoracotomy, with a mean difference of 0.68 (95% confidence interval, −1.89 to 3.26) between the two groups.

Analysis of secondary outcomes demonstrated that time spent undertaking moderate to vigorous physical activity was higher among participants receiving minithoracotomy at 6 weeks, although the treatment effect was small at an average of 9 minutes and was not different at 12 weeks.  

Postoperative length of hospital stay was reduced after minithoracotomy by 1 day, with a median of 5 days, compared with 6 days after sternotomy.

Although repair techniques were at the discretion of the surgeons and differed between the two procedures, high rates of valve repair and low rates of recurrent mitral regurgitation were observed in both groups. Cardiopulmonary bypass times were longer with minithoracotomy, but postoperative complications and adverse events were similar.

There was no difference between the two groups with respect to the prespecified safety outcome of death, repeat mitral valve surgery, or heart failure hospitalization up to 1 year, which occurred in 5.4% of patients undergoing minithoracotomy and 6.1% of those undergoing sternotomy.

“These findings can inform shared decision-making and treatment guidelines,” the authors conclude.
 

Approach ‘may appeal to patients’

In an editorial accompanying the publication of the study in JAMA, Maurice Enriquez-Sarano, MD, Minneapolis Heart Institute, Minnesota, says the results should be integrated into patient management.

“Mini-thoracotomy mitral repair carried low risk and was highly effective compared with sternotomy. It can thus be applied successfully by surgeons who achieve the necessary expertise,” he notes.

“Mini-thoracotomy may appeal to patients because the procedure is less disfiguring than sternotomy. The early (6-week) benefit, albeit small and transient, is important to patients,” he adds.

The study was funded by the United Kingdom’s National Institute for Health and Care Research. Dr. Akowuah reports no relevant financial relationships with industry. Dr. Enriquez-Sarano reports receiving consulting fees from Edwards Lifesciences, Artivion, ChemImage, HighLife, and Corcym.

A version of this article first appeared on Medscape.com.

The U.K. Mini Mitral trial, showing that mitral valve repair with the less invasive minithoracotomy approach achieved similar outcomes, compared with sternotomy, has now been published.

The trial, which was first presented earlier this year at the American College of Cardiology meeting, showed that minimally invasive mitral valve repair does not improve physical function at 12 weeks, compared with sternotomy, but outcomes at 1 year show minimally invasive repair is as safe and effective as sternotomy for degenerative mitral regurgitation.

The full results are now published online in JAMA.

The authors, led by Enoch Akowuah, MD, South Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom, explain that mitral valve repair surgery is the preferred treatment for patients with degenerative mitral regurgitation and is routinely performed via full sternotomy, enabling easy access to the heart, flexibility in myocardial protection strategies, and multiple ways of accessing the mitral valve and easing de-airing to prevent air emboli, which cause cerebrovascular accidents. 

However, the invasiveness of sternotomy is associated with delayed return to presurgery physical function levels and an increase in postoperative complications.

An alternative new video-guided minimally invasive approach involving a 4- to 7-cm lateral thoracotomy, completely avoiding sternotomy, has been developed, with the hope that it should speed physical recovery function after surgery and reduce postoperative complications and costs by reducing hospital stay.

Dr. Akowuah et al. note that uptake of minithoracotomy is variable, with low rates in the United States and the United Kingdom but high rates in Germany. They say that this variation is attributable to the absence of high-quality evidence from randomized trials demonstrating equivalent or superior benefits, compared with sternotomy, and there are also concerns that the increased technical complexity of minithoracotomy may impair the ability to repair complex valve lesions or increase perioperative complications, particularly vascular injuries and stroke.

The U.K. Mini Mitral trial was therefore conducted to compare the effectiveness and safety of minithoracotomy versus sternotomy mitral valve repair.

For the trial, 330 patients with degenerative mitral regurgitation were randomized to receive either minithoracotomy or sternotomy mitral valve repair performed by an expert surgeon.

The primary outcome was physical functioning and associated return to usual activities measured by change from baseline in the 36-Item Short Form Health Survey (SF-36) physical functioning scale 12 weeks after the surgery.  

This failed to show superiority of minithoracotomy, with a mean difference of 0.68 (95% confidence interval, −1.89 to 3.26) between the two groups.

Analysis of secondary outcomes demonstrated that time spent undertaking moderate to vigorous physical activity was higher among participants receiving minithoracotomy at 6 weeks, although the treatment effect was small at an average of 9 minutes and was not different at 12 weeks.  

Postoperative length of hospital stay was reduced after minithoracotomy by 1 day, with a median of 5 days, compared with 6 days after sternotomy.

Although repair techniques were at the discretion of the surgeons and differed between the two procedures, high rates of valve repair and low rates of recurrent mitral regurgitation were observed in both groups. Cardiopulmonary bypass times were longer with minithoracotomy, but postoperative complications and adverse events were similar.

There was no difference between the two groups with respect to the prespecified safety outcome of death, repeat mitral valve surgery, or heart failure hospitalization up to 1 year, which occurred in 5.4% of patients undergoing minithoracotomy and 6.1% of those undergoing sternotomy.

“These findings can inform shared decision-making and treatment guidelines,” the authors conclude.
 

Approach ‘may appeal to patients’

In an editorial accompanying the publication of the study in JAMA, Maurice Enriquez-Sarano, MD, Minneapolis Heart Institute, Minnesota, says the results should be integrated into patient management.

“Mini-thoracotomy mitral repair carried low risk and was highly effective compared with sternotomy. It can thus be applied successfully by surgeons who achieve the necessary expertise,” he notes.

“Mini-thoracotomy may appeal to patients because the procedure is less disfiguring than sternotomy. The early (6-week) benefit, albeit small and transient, is important to patients,” he adds.

The study was funded by the United Kingdom’s National Institute for Health and Care Research. Dr. Akowuah reports no relevant financial relationships with industry. Dr. Enriquez-Sarano reports receiving consulting fees from Edwards Lifesciences, Artivion, ChemImage, HighLife, and Corcym.

A version of this article first appeared on Medscape.com.

The U.K. Mini Mitral trial, showing that mitral valve repair with the less invasive minithoracotomy approach achieved similar outcomes, compared with sternotomy, has now been published.

The trial, which was first presented earlier this year at the American College of Cardiology meeting, showed that minimally invasive mitral valve repair does not improve physical function at 12 weeks, compared with sternotomy, but outcomes at 1 year show minimally invasive repair is as safe and effective as sternotomy for degenerative mitral regurgitation.

The full results are now published online in JAMA.

The authors, led by Enoch Akowuah, MD, South Tees Hospitals NHS Foundation Trust, Middlesbrough, United Kingdom, explain that mitral valve repair surgery is the preferred treatment for patients with degenerative mitral regurgitation and is routinely performed via full sternotomy, enabling easy access to the heart, flexibility in myocardial protection strategies, and multiple ways of accessing the mitral valve and easing de-airing to prevent air emboli, which cause cerebrovascular accidents. 

However, the invasiveness of sternotomy is associated with delayed return to presurgery physical function levels and an increase in postoperative complications.

An alternative new video-guided minimally invasive approach involving a 4- to 7-cm lateral thoracotomy, completely avoiding sternotomy, has been developed, with the hope that it should speed physical recovery function after surgery and reduce postoperative complications and costs by reducing hospital stay.

Dr. Akowuah et al. note that uptake of minithoracotomy is variable, with low rates in the United States and the United Kingdom but high rates in Germany. They say that this variation is attributable to the absence of high-quality evidence from randomized trials demonstrating equivalent or superior benefits, compared with sternotomy, and there are also concerns that the increased technical complexity of minithoracotomy may impair the ability to repair complex valve lesions or increase perioperative complications, particularly vascular injuries and stroke.

The U.K. Mini Mitral trial was therefore conducted to compare the effectiveness and safety of minithoracotomy versus sternotomy mitral valve repair.

For the trial, 330 patients with degenerative mitral regurgitation were randomized to receive either minithoracotomy or sternotomy mitral valve repair performed by an expert surgeon.

The primary outcome was physical functioning and associated return to usual activities measured by change from baseline in the 36-Item Short Form Health Survey (SF-36) physical functioning scale 12 weeks after the surgery.  

This failed to show superiority of minithoracotomy, with a mean difference of 0.68 (95% confidence interval, −1.89 to 3.26) between the two groups.

Analysis of secondary outcomes demonstrated that time spent undertaking moderate to vigorous physical activity was higher among participants receiving minithoracotomy at 6 weeks, although the treatment effect was small at an average of 9 minutes and was not different at 12 weeks.  

Postoperative length of hospital stay was reduced after minithoracotomy by 1 day, with a median of 5 days, compared with 6 days after sternotomy.

Although repair techniques were at the discretion of the surgeons and differed between the two procedures, high rates of valve repair and low rates of recurrent mitral regurgitation were observed in both groups. Cardiopulmonary bypass times were longer with minithoracotomy, but postoperative complications and adverse events were similar.

There was no difference between the two groups with respect to the prespecified safety outcome of death, repeat mitral valve surgery, or heart failure hospitalization up to 1 year, which occurred in 5.4% of patients undergoing minithoracotomy and 6.1% of those undergoing sternotomy.

“These findings can inform shared decision-making and treatment guidelines,” the authors conclude.
 

Approach ‘may appeal to patients’

In an editorial accompanying the publication of the study in JAMA, Maurice Enriquez-Sarano, MD, Minneapolis Heart Institute, Minnesota, says the results should be integrated into patient management.

“Mini-thoracotomy mitral repair carried low risk and was highly effective compared with sternotomy. It can thus be applied successfully by surgeons who achieve the necessary expertise,” he notes.

“Mini-thoracotomy may appeal to patients because the procedure is less disfiguring than sternotomy. The early (6-week) benefit, albeit small and transient, is important to patients,” he adds.

The study was funded by the United Kingdom’s National Institute for Health and Care Research. Dr. Akowuah reports no relevant financial relationships with industry. Dr. Enriquez-Sarano reports receiving consulting fees from Edwards Lifesciences, Artivion, ChemImage, HighLife, and Corcym.

A version of this article first appeared on Medscape.com.

Mounting evidence supports that chronic environmental exposure to low levels of lead, cadmium, and arsenic contribute significantly to cardiovascular disease (CVD), the American Heart Association says in a new scientific statement.

“In reality, identifying a new type of cardiovascular risk factor leads to more questions than answers,” Gervasio A. Lamas, MD, chair of the statement writing group, said in an interview.

“For the most part, as cardiologists, we are used to risk factors we can manage with antihypertensives, statins, weight loss, exercise, and avoidance of smoking. Unfortunately, the ubiquity of toxic metals and their multiple sources increases the complexity of potential treatment,” said Dr. Lamas, chairman of medicine and chief of the Columbia University division of cardiology at Mount Sinai Medical Center in Miami Beach, Fla.

The statement addressing contaminant metals as CV risk factors was published online in the Journal of the American Heart Association.
 

Involuntary exposure harms the heart

Exposure to contaminant metals most often happens involuntarily through air, water, soil, and food, and extensive industrial and public use, the writing group notes.

These contaminant metals interfere with critical intracellular reactions and functions, leading to oxidative stress and chronic inflammation; this in turn leads to endothelial dysfunction, hypertension, epigenetic dysregulation, dyslipidemia, and changes in myocardial excitation and contractile function, the authors point out.

Lead, cadmium, and arsenic have been linked to subclinical atherosclerosis, coronary artery stenosis and calcification, as well as to an increased risk for ischemic heart disease and stroke, left ventricular hypertrophy, and heart failure and peripheral artery disease.

Epidemiologic studies show that exposure to lead, cadmium, or arsenic is associated with cardiovascular death mostly attributable to ischemic heart disease. In the United States alone, one study suggested that more than 450,000 deaths annually could be attributed to lead exposure.

“This is a global issue in which lower-income communities are disproportionately exposed to toxic metals through contaminated air, water, and soil,” Ana Navas-Acien, MD, PhD, vice chair of the statement writing group, said in a news release.

“Addressing metal exposure in these populations may provide a strategy to reduce cardiovascular disease disparities and advance environmental justice,” adds Dr. Navas-Acien, professor of environmental health sciences at Columbia University, New York.

Dr. Lamas said in an interview that the writing group is “hopeful that there will be a multilevel response” to publication of the scientific statement.

“On the societal level, we believe more effort can be made to measure these pollutants and protect the public. On the physician level, knowledge of metal levels could become part of the routine risk evaluation of the cardiac patient. On the individual level, patients can try to avoid these pollutants, by knowing arsenic levels of well-water, lead and cadmium levels of drinking water, avoiding tobacco and vaping, and using filters when available or necessary,” Dr. Lamas said.

“On the scientific level, identifying ubiquitous pollutants should spur scientists and pharmaceutical companies to develop preventive and therapeutic approaches.”

Finally, clinical trials should be encouraged to assess existing drugs that can remove these atherogenic toxins from the body or treat their ill effects. One such trial is expected to be completed within a year, Dr. Lamas added.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Council on Epidemiology and Prevention; the Council on Cardiovascular and Stroke Nursing; the Council on Lifestyle and Cardiometabolic Health; the Council on Peripheral Vascular Disease; and the Council on the Kidney in Cardiovascular Disease.
 

A version of this article originally appeared on Medscape.com.

Mounting evidence supports that chronic environmental exposure to low levels of lead, cadmium, and arsenic contribute significantly to cardiovascular disease (CVD), the American Heart Association says in a new scientific statement.

“In reality, identifying a new type of cardiovascular risk factor leads to more questions than answers,” Gervasio A. Lamas, MD, chair of the statement writing group, said in an interview.

“For the most part, as cardiologists, we are used to risk factors we can manage with antihypertensives, statins, weight loss, exercise, and avoidance of smoking. Unfortunately, the ubiquity of toxic metals and their multiple sources increases the complexity of potential treatment,” said Dr. Lamas, chairman of medicine and chief of the Columbia University division of cardiology at Mount Sinai Medical Center in Miami Beach, Fla.

The statement addressing contaminant metals as CV risk factors was published online in the Journal of the American Heart Association.
 

Involuntary exposure harms the heart

Exposure to contaminant metals most often happens involuntarily through air, water, soil, and food, and extensive industrial and public use, the writing group notes.

These contaminant metals interfere with critical intracellular reactions and functions, leading to oxidative stress and chronic inflammation; this in turn leads to endothelial dysfunction, hypertension, epigenetic dysregulation, dyslipidemia, and changes in myocardial excitation and contractile function, the authors point out.

Lead, cadmium, and arsenic have been linked to subclinical atherosclerosis, coronary artery stenosis and calcification, as well as to an increased risk for ischemic heart disease and stroke, left ventricular hypertrophy, and heart failure and peripheral artery disease.

Epidemiologic studies show that exposure to lead, cadmium, or arsenic is associated with cardiovascular death mostly attributable to ischemic heart disease. In the United States alone, one study suggested that more than 450,000 deaths annually could be attributed to lead exposure.

“This is a global issue in which lower-income communities are disproportionately exposed to toxic metals through contaminated air, water, and soil,” Ana Navas-Acien, MD, PhD, vice chair of the statement writing group, said in a news release.

“Addressing metal exposure in these populations may provide a strategy to reduce cardiovascular disease disparities and advance environmental justice,” adds Dr. Navas-Acien, professor of environmental health sciences at Columbia University, New York.

Dr. Lamas said in an interview that the writing group is “hopeful that there will be a multilevel response” to publication of the scientific statement.

“On the societal level, we believe more effort can be made to measure these pollutants and protect the public. On the physician level, knowledge of metal levels could become part of the routine risk evaluation of the cardiac patient. On the individual level, patients can try to avoid these pollutants, by knowing arsenic levels of well-water, lead and cadmium levels of drinking water, avoiding tobacco and vaping, and using filters when available or necessary,” Dr. Lamas said.

“On the scientific level, identifying ubiquitous pollutants should spur scientists and pharmaceutical companies to develop preventive and therapeutic approaches.”

Finally, clinical trials should be encouraged to assess existing drugs that can remove these atherogenic toxins from the body or treat their ill effects. One such trial is expected to be completed within a year, Dr. Lamas added.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Council on Epidemiology and Prevention; the Council on Cardiovascular and Stroke Nursing; the Council on Lifestyle and Cardiometabolic Health; the Council on Peripheral Vascular Disease; and the Council on the Kidney in Cardiovascular Disease.
 

A version of this article originally appeared on Medscape.com.

Mounting evidence supports that chronic environmental exposure to low levels of lead, cadmium, and arsenic contribute significantly to cardiovascular disease (CVD), the American Heart Association says in a new scientific statement.

“In reality, identifying a new type of cardiovascular risk factor leads to more questions than answers,” Gervasio A. Lamas, MD, chair of the statement writing group, said in an interview.

“For the most part, as cardiologists, we are used to risk factors we can manage with antihypertensives, statins, weight loss, exercise, and avoidance of smoking. Unfortunately, the ubiquity of toxic metals and their multiple sources increases the complexity of potential treatment,” said Dr. Lamas, chairman of medicine and chief of the Columbia University division of cardiology at Mount Sinai Medical Center in Miami Beach, Fla.

The statement addressing contaminant metals as CV risk factors was published online in the Journal of the American Heart Association.
 

Involuntary exposure harms the heart

Exposure to contaminant metals most often happens involuntarily through air, water, soil, and food, and extensive industrial and public use, the writing group notes.

These contaminant metals interfere with critical intracellular reactions and functions, leading to oxidative stress and chronic inflammation; this in turn leads to endothelial dysfunction, hypertension, epigenetic dysregulation, dyslipidemia, and changes in myocardial excitation and contractile function, the authors point out.

Lead, cadmium, and arsenic have been linked to subclinical atherosclerosis, coronary artery stenosis and calcification, as well as to an increased risk for ischemic heart disease and stroke, left ventricular hypertrophy, and heart failure and peripheral artery disease.

Epidemiologic studies show that exposure to lead, cadmium, or arsenic is associated with cardiovascular death mostly attributable to ischemic heart disease. In the United States alone, one study suggested that more than 450,000 deaths annually could be attributed to lead exposure.

“This is a global issue in which lower-income communities are disproportionately exposed to toxic metals through contaminated air, water, and soil,” Ana Navas-Acien, MD, PhD, vice chair of the statement writing group, said in a news release.

“Addressing metal exposure in these populations may provide a strategy to reduce cardiovascular disease disparities and advance environmental justice,” adds Dr. Navas-Acien, professor of environmental health sciences at Columbia University, New York.

Dr. Lamas said in an interview that the writing group is “hopeful that there will be a multilevel response” to publication of the scientific statement.

“On the societal level, we believe more effort can be made to measure these pollutants and protect the public. On the physician level, knowledge of metal levels could become part of the routine risk evaluation of the cardiac patient. On the individual level, patients can try to avoid these pollutants, by knowing arsenic levels of well-water, lead and cadmium levels of drinking water, avoiding tobacco and vaping, and using filters when available or necessary,” Dr. Lamas said.

“On the scientific level, identifying ubiquitous pollutants should spur scientists and pharmaceutical companies to develop preventive and therapeutic approaches.”

Finally, clinical trials should be encouraged to assess existing drugs that can remove these atherogenic toxins from the body or treat their ill effects. One such trial is expected to be completed within a year, Dr. Lamas added.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Council on Epidemiology and Prevention; the Council on Cardiovascular and Stroke Nursing; the Council on Lifestyle and Cardiometabolic Health; the Council on Peripheral Vascular Disease; and the Council on the Kidney in Cardiovascular Disease.
 

A version of this article originally appeared on Medscape.com.

In metastatic breast cancer, a fixed dose of capecitabine given on a 7-day-on, 7-day-off schedule had similar efficacy and reduced adverse events compared with the standard 14-day-on, 7-day-off schedule, in a new study.

Both progression-free survival (PFS) and overall survival (OS) were similar between the two groups, but patients on the alternative schedule experienced fewer cases of hand-foot syndrome (HFS), diarrhea, and stomatitis, and also had fewer discontinuations and dose modifications.

The Food and Drug Administration–approved dose of capecitabine is 1,250 mg/m², but 14 days of treatment can lead to significant toxicity, said Qamar Khan, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. “Mathematical models applied to xenograft [animal model] data suggest that the maximum cytotoxic effect of capecitabine occurs after about 7 days of treatment, beyond which time only toxicity increases,” Dr. Khan said during his talk on the randomized control trial.

The researchers randomized 153 patients to receive a fixed 1,500-mg capecitabine dose twice per day on a 7-day-on, 7-day-off schedule (7/7), or the 1,250–mg/m² dose twice per day for 14 days followed by 7 days off (14/7). The median age was 60 years, and 85.6% were White, 8.5% were African American, 3.3% were Hispanic, 0.7% were American Indian or Alaskan Native, and 2.0% were other. With respect to disease characteristics, 44% had visceral metastasis, 78% were hormone receptor positive/HER2 negative, and 11% had triple-negative breast cancer. About two-thirds (65%) had received no prior chemotherapy.

Restricted mean survival time (RMST) at 36 months for PFS was 13.9 months in the 7/7 group and 14.6 months in the 14/7 group (difference, 0.7 months; 95.5% CI, –3.14 to 4.57 months). The objective response rate was 8.9% in the 7/7 group and 19.6% in the 14/7 group (P = .11). Median OS was 19.8 months in the 7/7 group and 17.5 months in the 14/7 group (hazard ratio, 0.76; P = .17). The RMST at 47 months for OS was 24.5 months in the 7/7 group and 20.9 months in the 14/7 group (difference, –3.6 months; 95% CI, –8.89 to 1.54 months).

The researchers found no differences in subgroup analyses by visceral metastasis, breast cancer subtype, or number of lines of previous therapy.

The toxicity profile of 7/7 was better with respect to grade 2-4 diarrhea (2.5% vs. 20.5%, P = .0008), grade 2-4 HFS (3.8% vs. 15.1%; P = .0019), and grade 2-4 mucositis (0% vs. 5.5%; P =.0001).
 

Findings back up clinical practice

“The fixed-dose capecitabine dosing is something that’s been done a lot in practice, because a lot of practitioners recognize that giving the drug for two weeks in a row with a week break is overly toxic, so it’s something we’ve been doing in the community for quite a while,” said Michael Danso, MD, who comoderated the session.

Still, the safety and efficacy data back up that general clinical practice. “There was a randomized trial and colon cancer that didn’t show [equivalent outcomes with the alternate dosing schedule]. So to see that it’s safe and effective in breast cancer is an important [finding],” said Dr. Danso, who is the Research Director at Virginia Oncology Associates, Norfolk.

During the question-and-answer following the talk, Jeffrey Kirshner, MD, a medical oncologist at Hematology-Oncology Associates of Central New York, East Syracuse, noted that his practice has used a similar schedule for years. “I really commend you for doing that study. It really supports what many of us in the real world have been doing for many years. We figured this out empirically, both upfront and when patients can’t tolerate [the 14/7 schedule].”
 

Fixed dose versus body surface area

Dr. Kirshner also said his practice uses a dose of 1 g/m² of body surface area on a 7/7 schedule rather than a fixed dose as was done in Dr. Khan’s study. “If you use the higher dose, you might have seen a higher response rate because many of our patients, as you know, have a body surface [BSA] area much greater than 1.5 g/m².”

Dr. Khan responded that there is little data available on BSA dosing. “We selected 1,500 mg because a lot of people are practicing that, and for convenience, and that most patients who started at a higher dose eventually wound up on a dose of 1,500 mg twice daily.”

Dr. Kirshner also pointed out that the study was conducted in a population with metastatic disease. “I think we need to emphasize that we do not use the 7/7 regimen in a potentially curative setting, such as the CREATE-X regimen for triple-negative [breast cancer].”

Dr. Khan agreed. “I would use the same dose as the CREATE-X trial in the adjuvant setting,” he responded.

Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen. Dr. Khan and Dr. Kirshner have no relevant financial disclosures.

In metastatic breast cancer, a fixed dose of capecitabine given on a 7-day-on, 7-day-off schedule had similar efficacy and reduced adverse events compared with the standard 14-day-on, 7-day-off schedule, in a new study.

Both progression-free survival (PFS) and overall survival (OS) were similar between the two groups, but patients on the alternative schedule experienced fewer cases of hand-foot syndrome (HFS), diarrhea, and stomatitis, and also had fewer discontinuations and dose modifications.

The Food and Drug Administration–approved dose of capecitabine is 1,250 mg/m², but 14 days of treatment can lead to significant toxicity, said Qamar Khan, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. “Mathematical models applied to xenograft [animal model] data suggest that the maximum cytotoxic effect of capecitabine occurs after about 7 days of treatment, beyond which time only toxicity increases,” Dr. Khan said during his talk on the randomized control trial.

The researchers randomized 153 patients to receive a fixed 1,500-mg capecitabine dose twice per day on a 7-day-on, 7-day-off schedule (7/7), or the 1,250–mg/m² dose twice per day for 14 days followed by 7 days off (14/7). The median age was 60 years, and 85.6% were White, 8.5% were African American, 3.3% were Hispanic, 0.7% were American Indian or Alaskan Native, and 2.0% were other. With respect to disease characteristics, 44% had visceral metastasis, 78% were hormone receptor positive/HER2 negative, and 11% had triple-negative breast cancer. About two-thirds (65%) had received no prior chemotherapy.

Restricted mean survival time (RMST) at 36 months for PFS was 13.9 months in the 7/7 group and 14.6 months in the 14/7 group (difference, 0.7 months; 95.5% CI, –3.14 to 4.57 months). The objective response rate was 8.9% in the 7/7 group and 19.6% in the 14/7 group (P = .11). Median OS was 19.8 months in the 7/7 group and 17.5 months in the 14/7 group (hazard ratio, 0.76; P = .17). The RMST at 47 months for OS was 24.5 months in the 7/7 group and 20.9 months in the 14/7 group (difference, –3.6 months; 95% CI, –8.89 to 1.54 months).

The researchers found no differences in subgroup analyses by visceral metastasis, breast cancer subtype, or number of lines of previous therapy.

The toxicity profile of 7/7 was better with respect to grade 2-4 diarrhea (2.5% vs. 20.5%, P = .0008), grade 2-4 HFS (3.8% vs. 15.1%; P = .0019), and grade 2-4 mucositis (0% vs. 5.5%; P =.0001).
 

Findings back up clinical practice

“The fixed-dose capecitabine dosing is something that’s been done a lot in practice, because a lot of practitioners recognize that giving the drug for two weeks in a row with a week break is overly toxic, so it’s something we’ve been doing in the community for quite a while,” said Michael Danso, MD, who comoderated the session.

Still, the safety and efficacy data back up that general clinical practice. “There was a randomized trial and colon cancer that didn’t show [equivalent outcomes with the alternate dosing schedule]. So to see that it’s safe and effective in breast cancer is an important [finding],” said Dr. Danso, who is the Research Director at Virginia Oncology Associates, Norfolk.

During the question-and-answer following the talk, Jeffrey Kirshner, MD, a medical oncologist at Hematology-Oncology Associates of Central New York, East Syracuse, noted that his practice has used a similar schedule for years. “I really commend you for doing that study. It really supports what many of us in the real world have been doing for many years. We figured this out empirically, both upfront and when patients can’t tolerate [the 14/7 schedule].”
 

Fixed dose versus body surface area

Dr. Kirshner also said his practice uses a dose of 1 g/m² of body surface area on a 7/7 schedule rather than a fixed dose as was done in Dr. Khan’s study. “If you use the higher dose, you might have seen a higher response rate because many of our patients, as you know, have a body surface [BSA] area much greater than 1.5 g/m².”

Dr. Khan responded that there is little data available on BSA dosing. “We selected 1,500 mg because a lot of people are practicing that, and for convenience, and that most patients who started at a higher dose eventually wound up on a dose of 1,500 mg twice daily.”

Dr. Kirshner also pointed out that the study was conducted in a population with metastatic disease. “I think we need to emphasize that we do not use the 7/7 regimen in a potentially curative setting, such as the CREATE-X regimen for triple-negative [breast cancer].”

Dr. Khan agreed. “I would use the same dose as the CREATE-X trial in the adjuvant setting,” he responded.

Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen. Dr. Khan and Dr. Kirshner have no relevant financial disclosures.

In metastatic breast cancer, a fixed dose of capecitabine given on a 7-day-on, 7-day-off schedule had similar efficacy and reduced adverse events compared with the standard 14-day-on, 7-day-off schedule, in a new study.

Both progression-free survival (PFS) and overall survival (OS) were similar between the two groups, but patients on the alternative schedule experienced fewer cases of hand-foot syndrome (HFS), diarrhea, and stomatitis, and also had fewer discontinuations and dose modifications.

The Food and Drug Administration–approved dose of capecitabine is 1,250 mg/m², but 14 days of treatment can lead to significant toxicity, said Qamar Khan, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. “Mathematical models applied to xenograft [animal model] data suggest that the maximum cytotoxic effect of capecitabine occurs after about 7 days of treatment, beyond which time only toxicity increases,” Dr. Khan said during his talk on the randomized control trial.

The researchers randomized 153 patients to receive a fixed 1,500-mg capecitabine dose twice per day on a 7-day-on, 7-day-off schedule (7/7), or the 1,250–mg/m² dose twice per day for 14 days followed by 7 days off (14/7). The median age was 60 years, and 85.6% were White, 8.5% were African American, 3.3% were Hispanic, 0.7% were American Indian or Alaskan Native, and 2.0% were other. With respect to disease characteristics, 44% had visceral metastasis, 78% were hormone receptor positive/HER2 negative, and 11% had triple-negative breast cancer. About two-thirds (65%) had received no prior chemotherapy.

Restricted mean survival time (RMST) at 36 months for PFS was 13.9 months in the 7/7 group and 14.6 months in the 14/7 group (difference, 0.7 months; 95.5% CI, –3.14 to 4.57 months). The objective response rate was 8.9% in the 7/7 group and 19.6% in the 14/7 group (P = .11). Median OS was 19.8 months in the 7/7 group and 17.5 months in the 14/7 group (hazard ratio, 0.76; P = .17). The RMST at 47 months for OS was 24.5 months in the 7/7 group and 20.9 months in the 14/7 group (difference, –3.6 months; 95% CI, –8.89 to 1.54 months).

The researchers found no differences in subgroup analyses by visceral metastasis, breast cancer subtype, or number of lines of previous therapy.

The toxicity profile of 7/7 was better with respect to grade 2-4 diarrhea (2.5% vs. 20.5%, P = .0008), grade 2-4 HFS (3.8% vs. 15.1%; P = .0019), and grade 2-4 mucositis (0% vs. 5.5%; P =.0001).
 

Findings back up clinical practice

“The fixed-dose capecitabine dosing is something that’s been done a lot in practice, because a lot of practitioners recognize that giving the drug for two weeks in a row with a week break is overly toxic, so it’s something we’ve been doing in the community for quite a while,” said Michael Danso, MD, who comoderated the session.

Still, the safety and efficacy data back up that general clinical practice. “There was a randomized trial and colon cancer that didn’t show [equivalent outcomes with the alternate dosing schedule]. So to see that it’s safe and effective in breast cancer is an important [finding],” said Dr. Danso, who is the Research Director at Virginia Oncology Associates, Norfolk.

During the question-and-answer following the talk, Jeffrey Kirshner, MD, a medical oncologist at Hematology-Oncology Associates of Central New York, East Syracuse, noted that his practice has used a similar schedule for years. “I really commend you for doing that study. It really supports what many of us in the real world have been doing for many years. We figured this out empirically, both upfront and when patients can’t tolerate [the 14/7 schedule].”
 

Fixed dose versus body surface area

Dr. Kirshner also said his practice uses a dose of 1 g/m² of body surface area on a 7/7 schedule rather than a fixed dose as was done in Dr. Khan’s study. “If you use the higher dose, you might have seen a higher response rate because many of our patients, as you know, have a body surface [BSA] area much greater than 1.5 g/m².”

Dr. Khan responded that there is little data available on BSA dosing. “We selected 1,500 mg because a lot of people are practicing that, and for convenience, and that most patients who started at a higher dose eventually wound up on a dose of 1,500 mg twice daily.”

Dr. Kirshner also pointed out that the study was conducted in a population with metastatic disease. “I think we need to emphasize that we do not use the 7/7 regimen in a potentially curative setting, such as the CREATE-X regimen for triple-negative [breast cancer].”

Dr. Khan agreed. “I would use the same dose as the CREATE-X trial in the adjuvant setting,” he responded.

Dr. Danso has received honoraria from Amgen and has consulted or advised Immunomedics, Novartis, Pfizer, and Seagen. Dr. Khan and Dr. Kirshner have no relevant financial disclosures.

MUNICH – Patients undergoing carotid artery stenting (CAS) may have fewer ischemic lesions and a lower lesion burden if they are given the reversible P2Y12 receptor antagonist ticagrelor rather than clopidogrel, another P2Y12 inhibitor, prior to the procedure, secondary endpoint results of the PRECISE-MRI trial suggest.

More than 200 patients with carotid artery stenosis underwent MRI and were randomized to ticagrelor or clopidogrel before undergoing CAS. They then had two follow-up MRIs to assess the presence of emergent ischemic lesions.

Although the trial, which was stopped early, failed to show a difference between the two treatments in the primary endpoint – occurrence of at least one ischemic lesion – it did show that ticagrelor was associated with significant reductions in secondary endpoints including the total number and total volume of new lesions.

There were also significantly fewer cases of a composite of adverse clinical events with ticagrelor versus clopidogrel, but no difference in rates of hemorrhagic bleeds.

The research was presented at the annual European Stroke Organisation Conference .

Highlighting the failure of the trial to meet its primary endpoint, study presenter Leo Bonati, MD, head of the Stroke Center, Rena Rheinfelden, University Hospital Basel (Switzerland), pointed out that the proportion of patients with one or more ischemic brain lesions was “much higher than expected.”

Based on the secondary outcomes, the study nevertheless indicates that, “compared with clopidogrel, ticagrelor reduces the total burden of ischemic brain lesions occurring during CAS,” he said.

Ticagrelor is therefore a “safe alternative to clopidogrel as an add-on to aspirin to cover carotid artery stent procedures.”

Dr. Bonati cautioned, however, that the findings are preliminary.
 

‘Promising’ results

Session cochair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the stroke unit, department of neurology, Oslo University Hospital, called the results “interesting” and “promising.”

She said in an interview that they “also provide us with an additional option” in the management of patients undergoing CAS.

Dr. Sandset suggested that “it may have been a little bit hard to prove the primary endpoint” chosen for the trial, but believes that the secondary endpoint results “are very interesting.”

“Of course, we would need more data and further trials to provide some reassurance that we can use ticagrelor in this fashion,” she said.
 

Major complication

Dr. Bonati began by noting that the major procedural complication of CAS is embolic stroke, but this may be prevented with optimized antiplatelet therapy.

Previous studies have shown that ticagrelor is superior to clopidogrel as an add-on to aspirin in reducing rates of major adverse cardiovascular events in acute coronary syndrome patients undergoing percutaneous coronary intervention.

Adding the drug to aspirin is also superior to aspirin alone in preventing recurrent stroke in patients with minor stroke or transient ischemic attack, Dr. Bonati said.

To examine whether ticagrelor is superior to clopidogrel as an add-on to aspirin in preventing ischemic brain lesions during CAS, the team conducted a randomized, open, active-controlled trial.

They recruited patients with ≥ 50% symptomatic or asymptomatic carotid stenosis undergoing CAS in line with local guidelines and performed a baseline MRI scan and clinical examination.

The patients were then randomized to ticagrelor or clopidogrel plus aspirin 1-3 days before undergoing CAS. A second MRI and clinical examination, as well as an ultrasound scan, was performed at 1 to 3 days post-CAS, with a third set of examinations performed at 28-32 days after the procedure.

The study included 14 sites in Belgium, Germany, Italy, the Netherlands, Switzerland, and the United Kingdom. Enrollment was stopped after 209 of the originally planned 370 patients, “due to slow recruitment and a lack of further funding,” Dr. Bonati said.

Of those, 207 patients were included in the intention-to-treat safety analysis, and 172 in the per-protocol efficacy analysis.

The mean age of the patients was 69.0-69.5 years in the two treatment groups, and 67%-71% were male. Dr. Bonati noted that 52%-55% of the patients had symptomatic stenosis, and that in 83%-88% the stenosis was severe.

The majority (79%-82%) of patients had hypertension, alongside hypercholesterolemia, at 76% in both treatment groups.

Dr. Bonati showed that there was no significant difference in the primary efficacy outcome of the presence of at least new ischemic brain lesion on the second or third MRI, at 74.7% for patients given ticagrelor versus 79.8% with clopidogrel, or a relative risk of 0.94 (95% confidence interval, 0.79-1.10; P = .43).

However, there was a significant reduction in the number of new ischemic lesions, at a median of 2 (interquartile range, 0.5-5.5) with ticagrelor versus 3 with clopidogrel (IQR, 1-8), or an exponential beta value of 0.63 (95% CI, 0.42-0.95; P = .027).

Ticagrelor was also associated with a significant reduction in the total volume of lesions, at a median of 66 mcL (IQR, 2.5-2.19) versus 91 mcL (IQR, 25-394) for clopidogrel, or an exponential beta value of 0.30 (95% CI, 0.10-0.92; P = .030).

Patients assigned to ticagrelor also had a significantly lower rate of the primary clinical safety outcome, a composite of stroke, myocardial infarction, major bleeding, or cardiovascular death, at 2.9% versus 7.8% (relative risk, 0.36; 95% CI, 0.08-1.20). This was driven by a reduction in rates of post-CAS stroke.

Dr. Bonati noted that there was no significant difference in the presence of at least one hemorrhagic lesion after CAS, at 42.7% with ticagrelor and 47.6% in the clopidogrel group (RR, 0.90; 95% CI, 0.63-1.26).

There was also a similar rate of microbleeds between the two treatment groups, at 36.6% in patients given ticagrelor and 47.6% in those assigned to clopidogrel.

The study was investigator initiated and funded by an unrestricted research grant from AstraZeneca. No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

MUNICH – Patients undergoing carotid artery stenting (CAS) may have fewer ischemic lesions and a lower lesion burden if they are given the reversible P2Y12 receptor antagonist ticagrelor rather than clopidogrel, another P2Y12 inhibitor, prior to the procedure, secondary endpoint results of the PRECISE-MRI trial suggest.

More than 200 patients with carotid artery stenosis underwent MRI and were randomized to ticagrelor or clopidogrel before undergoing CAS. They then had two follow-up MRIs to assess the presence of emergent ischemic lesions.

Although the trial, which was stopped early, failed to show a difference between the two treatments in the primary endpoint – occurrence of at least one ischemic lesion – it did show that ticagrelor was associated with significant reductions in secondary endpoints including the total number and total volume of new lesions.

There were also significantly fewer cases of a composite of adverse clinical events with ticagrelor versus clopidogrel, but no difference in rates of hemorrhagic bleeds.

The research was presented at the annual European Stroke Organisation Conference .

Highlighting the failure of the trial to meet its primary endpoint, study presenter Leo Bonati, MD, head of the Stroke Center, Rena Rheinfelden, University Hospital Basel (Switzerland), pointed out that the proportion of patients with one or more ischemic brain lesions was “much higher than expected.”

Based on the secondary outcomes, the study nevertheless indicates that, “compared with clopidogrel, ticagrelor reduces the total burden of ischemic brain lesions occurring during CAS,” he said.

Ticagrelor is therefore a “safe alternative to clopidogrel as an add-on to aspirin to cover carotid artery stent procedures.”

Dr. Bonati cautioned, however, that the findings are preliminary.
 

‘Promising’ results

Session cochair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the stroke unit, department of neurology, Oslo University Hospital, called the results “interesting” and “promising.”

She said in an interview that they “also provide us with an additional option” in the management of patients undergoing CAS.

Dr. Sandset suggested that “it may have been a little bit hard to prove the primary endpoint” chosen for the trial, but believes that the secondary endpoint results “are very interesting.”

“Of course, we would need more data and further trials to provide some reassurance that we can use ticagrelor in this fashion,” she said.
 

Major complication

Dr. Bonati began by noting that the major procedural complication of CAS is embolic stroke, but this may be prevented with optimized antiplatelet therapy.

Previous studies have shown that ticagrelor is superior to clopidogrel as an add-on to aspirin in reducing rates of major adverse cardiovascular events in acute coronary syndrome patients undergoing percutaneous coronary intervention.

Adding the drug to aspirin is also superior to aspirin alone in preventing recurrent stroke in patients with minor stroke or transient ischemic attack, Dr. Bonati said.

To examine whether ticagrelor is superior to clopidogrel as an add-on to aspirin in preventing ischemic brain lesions during CAS, the team conducted a randomized, open, active-controlled trial.

They recruited patients with ≥ 50% symptomatic or asymptomatic carotid stenosis undergoing CAS in line with local guidelines and performed a baseline MRI scan and clinical examination.

The patients were then randomized to ticagrelor or clopidogrel plus aspirin 1-3 days before undergoing CAS. A second MRI and clinical examination, as well as an ultrasound scan, was performed at 1 to 3 days post-CAS, with a third set of examinations performed at 28-32 days after the procedure.

The study included 14 sites in Belgium, Germany, Italy, the Netherlands, Switzerland, and the United Kingdom. Enrollment was stopped after 209 of the originally planned 370 patients, “due to slow recruitment and a lack of further funding,” Dr. Bonati said.

Of those, 207 patients were included in the intention-to-treat safety analysis, and 172 in the per-protocol efficacy analysis.

The mean age of the patients was 69.0-69.5 years in the two treatment groups, and 67%-71% were male. Dr. Bonati noted that 52%-55% of the patients had symptomatic stenosis, and that in 83%-88% the stenosis was severe.

The majority (79%-82%) of patients had hypertension, alongside hypercholesterolemia, at 76% in both treatment groups.

Dr. Bonati showed that there was no significant difference in the primary efficacy outcome of the presence of at least new ischemic brain lesion on the second or third MRI, at 74.7% for patients given ticagrelor versus 79.8% with clopidogrel, or a relative risk of 0.94 (95% confidence interval, 0.79-1.10; P = .43).

However, there was a significant reduction in the number of new ischemic lesions, at a median of 2 (interquartile range, 0.5-5.5) with ticagrelor versus 3 with clopidogrel (IQR, 1-8), or an exponential beta value of 0.63 (95% CI, 0.42-0.95; P = .027).

Ticagrelor was also associated with a significant reduction in the total volume of lesions, at a median of 66 mcL (IQR, 2.5-2.19) versus 91 mcL (IQR, 25-394) for clopidogrel, or an exponential beta value of 0.30 (95% CI, 0.10-0.92; P = .030).

Patients assigned to ticagrelor also had a significantly lower rate of the primary clinical safety outcome, a composite of stroke, myocardial infarction, major bleeding, or cardiovascular death, at 2.9% versus 7.8% (relative risk, 0.36; 95% CI, 0.08-1.20). This was driven by a reduction in rates of post-CAS stroke.

Dr. Bonati noted that there was no significant difference in the presence of at least one hemorrhagic lesion after CAS, at 42.7% with ticagrelor and 47.6% in the clopidogrel group (RR, 0.90; 95% CI, 0.63-1.26).

There was also a similar rate of microbleeds between the two treatment groups, at 36.6% in patients given ticagrelor and 47.6% in those assigned to clopidogrel.

The study was investigator initiated and funded by an unrestricted research grant from AstraZeneca. No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

MUNICH – Patients undergoing carotid artery stenting (CAS) may have fewer ischemic lesions and a lower lesion burden if they are given the reversible P2Y12 receptor antagonist ticagrelor rather than clopidogrel, another P2Y12 inhibitor, prior to the procedure, secondary endpoint results of the PRECISE-MRI trial suggest.

More than 200 patients with carotid artery stenosis underwent MRI and were randomized to ticagrelor or clopidogrel before undergoing CAS. They then had two follow-up MRIs to assess the presence of emergent ischemic lesions.

Although the trial, which was stopped early, failed to show a difference between the two treatments in the primary endpoint – occurrence of at least one ischemic lesion – it did show that ticagrelor was associated with significant reductions in secondary endpoints including the total number and total volume of new lesions.

There were also significantly fewer cases of a composite of adverse clinical events with ticagrelor versus clopidogrel, but no difference in rates of hemorrhagic bleeds.

The research was presented at the annual European Stroke Organisation Conference .

Highlighting the failure of the trial to meet its primary endpoint, study presenter Leo Bonati, MD, head of the Stroke Center, Rena Rheinfelden, University Hospital Basel (Switzerland), pointed out that the proportion of patients with one or more ischemic brain lesions was “much higher than expected.”

Based on the secondary outcomes, the study nevertheless indicates that, “compared with clopidogrel, ticagrelor reduces the total burden of ischemic brain lesions occurring during CAS,” he said.

Ticagrelor is therefore a “safe alternative to clopidogrel as an add-on to aspirin to cover carotid artery stent procedures.”

Dr. Bonati cautioned, however, that the findings are preliminary.
 

‘Promising’ results

Session cochair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the stroke unit, department of neurology, Oslo University Hospital, called the results “interesting” and “promising.”

She said in an interview that they “also provide us with an additional option” in the management of patients undergoing CAS.

Dr. Sandset suggested that “it may have been a little bit hard to prove the primary endpoint” chosen for the trial, but believes that the secondary endpoint results “are very interesting.”

“Of course, we would need more data and further trials to provide some reassurance that we can use ticagrelor in this fashion,” she said.
 

Major complication

Dr. Bonati began by noting that the major procedural complication of CAS is embolic stroke, but this may be prevented with optimized antiplatelet therapy.

Previous studies have shown that ticagrelor is superior to clopidogrel as an add-on to aspirin in reducing rates of major adverse cardiovascular events in acute coronary syndrome patients undergoing percutaneous coronary intervention.

Adding the drug to aspirin is also superior to aspirin alone in preventing recurrent stroke in patients with minor stroke or transient ischemic attack, Dr. Bonati said.

To examine whether ticagrelor is superior to clopidogrel as an add-on to aspirin in preventing ischemic brain lesions during CAS, the team conducted a randomized, open, active-controlled trial.

They recruited patients with ≥ 50% symptomatic or asymptomatic carotid stenosis undergoing CAS in line with local guidelines and performed a baseline MRI scan and clinical examination.

The patients were then randomized to ticagrelor or clopidogrel plus aspirin 1-3 days before undergoing CAS. A second MRI and clinical examination, as well as an ultrasound scan, was performed at 1 to 3 days post-CAS, with a third set of examinations performed at 28-32 days after the procedure.

The study included 14 sites in Belgium, Germany, Italy, the Netherlands, Switzerland, and the United Kingdom. Enrollment was stopped after 209 of the originally planned 370 patients, “due to slow recruitment and a lack of further funding,” Dr. Bonati said.

Of those, 207 patients were included in the intention-to-treat safety analysis, and 172 in the per-protocol efficacy analysis.

The mean age of the patients was 69.0-69.5 years in the two treatment groups, and 67%-71% were male. Dr. Bonati noted that 52%-55% of the patients had symptomatic stenosis, and that in 83%-88% the stenosis was severe.

The majority (79%-82%) of patients had hypertension, alongside hypercholesterolemia, at 76% in both treatment groups.

Dr. Bonati showed that there was no significant difference in the primary efficacy outcome of the presence of at least new ischemic brain lesion on the second or third MRI, at 74.7% for patients given ticagrelor versus 79.8% with clopidogrel, or a relative risk of 0.94 (95% confidence interval, 0.79-1.10; P = .43).

However, there was a significant reduction in the number of new ischemic lesions, at a median of 2 (interquartile range, 0.5-5.5) with ticagrelor versus 3 with clopidogrel (IQR, 1-8), or an exponential beta value of 0.63 (95% CI, 0.42-0.95; P = .027).

Ticagrelor was also associated with a significant reduction in the total volume of lesions, at a median of 66 mcL (IQR, 2.5-2.19) versus 91 mcL (IQR, 25-394) for clopidogrel, or an exponential beta value of 0.30 (95% CI, 0.10-0.92; P = .030).

Patients assigned to ticagrelor also had a significantly lower rate of the primary clinical safety outcome, a composite of stroke, myocardial infarction, major bleeding, or cardiovascular death, at 2.9% versus 7.8% (relative risk, 0.36; 95% CI, 0.08-1.20). This was driven by a reduction in rates of post-CAS stroke.

Dr. Bonati noted that there was no significant difference in the presence of at least one hemorrhagic lesion after CAS, at 42.7% with ticagrelor and 47.6% in the clopidogrel group (RR, 0.90; 95% CI, 0.63-1.26).

There was also a similar rate of microbleeds between the two treatment groups, at 36.6% in patients given ticagrelor and 47.6% in those assigned to clopidogrel.

The study was investigator initiated and funded by an unrestricted research grant from AstraZeneca. No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

A new study provides novel insights into why light to moderate alcohol consumption may be associated with reduced cardiovascular disease (CVD) risk.

The study shows that light to moderate drinking was associated with lower major adverse cardiovascular events (MACE), and this was partly mediated by decreased stress signaling in the brain.

In addition, the benefit of light to moderate drinking with respect to MACE was most pronounced among people with a history of anxiety, a condition known to be associated with higher stress signaling in the brain.

However, the apparent CVD benefits of light to moderate drinking were counterbalanced by an increased risk of cancer.

“There is no safe level of alcohol consumption,” senior author and cardiologist Ahmed Tawakol, MD, codirector of the Cardiovascular Imaging Research Center at Massachusetts General Hospital, Boston, said in an interview.

“We see cancer risk even at the level that we see some protection from heart disease. And higher amounts of alcohol clearly increase heart disease risk,” Dr. Tawakol said.

The study was published online in the Journal of the American College of Cardiology.
 

Clear mechanistic link

Chronic stress is associated with MACE via stress-related neural network activity (SNA). Light to moderate alcohol consumption has been linked to lower MACE risk, but the mechanisms behind this connection remain unclear.

“We know that when the neural centers of stress are activated, they trigger downstream changes that result in heart disease. And we’ve long appreciated that alcohol in the short term reduces stress, so we hypothesized that maybe alcohol impacts those stress systems chronically and that might explain its cardiovascular effects,” Dr. Tawakol explained.

The study included roughly 53,000 adults (mean age, 60 years; 60% women) from the Mass General Brigham Biobank. The researchers first evaluated the relationship between light to moderate alcohol consumption and MACE after adjusting for a range of genetic, clinical, lifestyle, and socioeconomic factors.

During mean follow-up of 3.4 years, 1,914 individuals experienced MACE. Light to moderate alcohol consumption (compared to none/minimal) was associated with lower MACE risk (hazard ratio [HR], 0.786; 95% confidence interval [CI], 0.717-0.862; P < .0001) after adjustment for cardiovascular risk factors.

The researchers then studied a subset of 713 individuals who had undergone previous PET/CT brain imaging (primarily for cancer surveillance) to determine the effect of light to moderate alcohol consumption on resting SNA.

They found that light to moderate alcohol consumption correlated with decreased SNA (standardized beta, –0.192; 95% CI, –0.338 to 0.046; P = .01). Lower SNA partially mediated the beneficial effect of light to moderate alcohol intake on MACE risk (odds ratio [OR], –0.040; 95% CI, –0.097 to –0.003; P < .05).

Light to moderate alcohol consumption was associated with larger decreases in MACE risk among individuals with a history of anxiety (HR, 0.60; 95% CI, 0.50-0.72, vs. HR, 1.78; 95% CI, 0.73-0.80; P = .003).

The coauthors of an editorial say the discovery of a “new possible mechanism of action” for why light to moderate alcohol consumption might protect the heart “deserves closer attention in future investigations.”

However, Giovanni de Gaetano, MD, PhD, department of epidemiology and prevention, IRCCS NEUROMED, Pozzilli, Italy, one of the authors, emphasized that individuals who consume alcohol should not “exceed the recommended daily dose limits suggested in many countries and that no abstainer should start to drink, even in moderation, solely for the purpose of improving his/her health outcomes.”

Dr. Tawakol and colleagues said that, given alcohol’s adverse health effects, such as heightened cancer risk, new interventions that have positive effects on the neurobiology of stress but without the harmful effects of alcohol are needed.

To that end, they are studying the effect of exercise, stress-reduction interventions such as meditation, and pharmacologic therapies on stress-associated neural networks, and how they might induce CV benefits.

Dr. Tawakol said in an interview that one “additional important message is that anxiety and other related conditions like depression have really substantial health consequences, including increased MACE. Safer interventions that reduce anxiety may yet prove to reduce the risk of heart disease very nicely.”

The study was supported by the National Institutes of Health. Dr. Tawakol and Dr. de Gaetano have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A new study provides novel insights into why light to moderate alcohol consumption may be associated with reduced cardiovascular disease (CVD) risk.

The study shows that light to moderate drinking was associated with lower major adverse cardiovascular events (MACE), and this was partly mediated by decreased stress signaling in the brain.

In addition, the benefit of light to moderate drinking with respect to MACE was most pronounced among people with a history of anxiety, a condition known to be associated with higher stress signaling in the brain.

However, the apparent CVD benefits of light to moderate drinking were counterbalanced by an increased risk of cancer.

“There is no safe level of alcohol consumption,” senior author and cardiologist Ahmed Tawakol, MD, codirector of the Cardiovascular Imaging Research Center at Massachusetts General Hospital, Boston, said in an interview.

“We see cancer risk even at the level that we see some protection from heart disease. And higher amounts of alcohol clearly increase heart disease risk,” Dr. Tawakol said.

The study was published online in the Journal of the American College of Cardiology.
 

Clear mechanistic link

Chronic stress is associated with MACE via stress-related neural network activity (SNA). Light to moderate alcohol consumption has been linked to lower MACE risk, but the mechanisms behind this connection remain unclear.

“We know that when the neural centers of stress are activated, they trigger downstream changes that result in heart disease. And we’ve long appreciated that alcohol in the short term reduces stress, so we hypothesized that maybe alcohol impacts those stress systems chronically and that might explain its cardiovascular effects,” Dr. Tawakol explained.

The study included roughly 53,000 adults (mean age, 60 years; 60% women) from the Mass General Brigham Biobank. The researchers first evaluated the relationship between light to moderate alcohol consumption and MACE after adjusting for a range of genetic, clinical, lifestyle, and socioeconomic factors.

During mean follow-up of 3.4 years, 1,914 individuals experienced MACE. Light to moderate alcohol consumption (compared to none/minimal) was associated with lower MACE risk (hazard ratio [HR], 0.786; 95% confidence interval [CI], 0.717-0.862; P < .0001) after adjustment for cardiovascular risk factors.

The researchers then studied a subset of 713 individuals who had undergone previous PET/CT brain imaging (primarily for cancer surveillance) to determine the effect of light to moderate alcohol consumption on resting SNA.

They found that light to moderate alcohol consumption correlated with decreased SNA (standardized beta, –0.192; 95% CI, –0.338 to 0.046; P = .01). Lower SNA partially mediated the beneficial effect of light to moderate alcohol intake on MACE risk (odds ratio [OR], –0.040; 95% CI, –0.097 to –0.003; P < .05).

Light to moderate alcohol consumption was associated with larger decreases in MACE risk among individuals with a history of anxiety (HR, 0.60; 95% CI, 0.50-0.72, vs. HR, 1.78; 95% CI, 0.73-0.80; P = .003).

The coauthors of an editorial say the discovery of a “new possible mechanism of action” for why light to moderate alcohol consumption might protect the heart “deserves closer attention in future investigations.”

However, Giovanni de Gaetano, MD, PhD, department of epidemiology and prevention, IRCCS NEUROMED, Pozzilli, Italy, one of the authors, emphasized that individuals who consume alcohol should not “exceed the recommended daily dose limits suggested in many countries and that no abstainer should start to drink, even in moderation, solely for the purpose of improving his/her health outcomes.”

Dr. Tawakol and colleagues said that, given alcohol’s adverse health effects, such as heightened cancer risk, new interventions that have positive effects on the neurobiology of stress but without the harmful effects of alcohol are needed.

To that end, they are studying the effect of exercise, stress-reduction interventions such as meditation, and pharmacologic therapies on stress-associated neural networks, and how they might induce CV benefits.

Dr. Tawakol said in an interview that one “additional important message is that anxiety and other related conditions like depression have really substantial health consequences, including increased MACE. Safer interventions that reduce anxiety may yet prove to reduce the risk of heart disease very nicely.”

The study was supported by the National Institutes of Health. Dr. Tawakol and Dr. de Gaetano have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A new study provides novel insights into why light to moderate alcohol consumption may be associated with reduced cardiovascular disease (CVD) risk.

The study shows that light to moderate drinking was associated with lower major adverse cardiovascular events (MACE), and this was partly mediated by decreased stress signaling in the brain.

In addition, the benefit of light to moderate drinking with respect to MACE was most pronounced among people with a history of anxiety, a condition known to be associated with higher stress signaling in the brain.

However, the apparent CVD benefits of light to moderate drinking were counterbalanced by an increased risk of cancer.

“There is no safe level of alcohol consumption,” senior author and cardiologist Ahmed Tawakol, MD, codirector of the Cardiovascular Imaging Research Center at Massachusetts General Hospital, Boston, said in an interview.

“We see cancer risk even at the level that we see some protection from heart disease. And higher amounts of alcohol clearly increase heart disease risk,” Dr. Tawakol said.

The study was published online in the Journal of the American College of Cardiology.
 

Clear mechanistic link

Chronic stress is associated with MACE via stress-related neural network activity (SNA). Light to moderate alcohol consumption has been linked to lower MACE risk, but the mechanisms behind this connection remain unclear.

“We know that when the neural centers of stress are activated, they trigger downstream changes that result in heart disease. And we’ve long appreciated that alcohol in the short term reduces stress, so we hypothesized that maybe alcohol impacts those stress systems chronically and that might explain its cardiovascular effects,” Dr. Tawakol explained.

The study included roughly 53,000 adults (mean age, 60 years; 60% women) from the Mass General Brigham Biobank. The researchers first evaluated the relationship between light to moderate alcohol consumption and MACE after adjusting for a range of genetic, clinical, lifestyle, and socioeconomic factors.

During mean follow-up of 3.4 years, 1,914 individuals experienced MACE. Light to moderate alcohol consumption (compared to none/minimal) was associated with lower MACE risk (hazard ratio [HR], 0.786; 95% confidence interval [CI], 0.717-0.862; P < .0001) after adjustment for cardiovascular risk factors.

The researchers then studied a subset of 713 individuals who had undergone previous PET/CT brain imaging (primarily for cancer surveillance) to determine the effect of light to moderate alcohol consumption on resting SNA.

They found that light to moderate alcohol consumption correlated with decreased SNA (standardized beta, –0.192; 95% CI, –0.338 to 0.046; P = .01). Lower SNA partially mediated the beneficial effect of light to moderate alcohol intake on MACE risk (odds ratio [OR], –0.040; 95% CI, –0.097 to –0.003; P < .05).

Light to moderate alcohol consumption was associated with larger decreases in MACE risk among individuals with a history of anxiety (HR, 0.60; 95% CI, 0.50-0.72, vs. HR, 1.78; 95% CI, 0.73-0.80; P = .003).

The coauthors of an editorial say the discovery of a “new possible mechanism of action” for why light to moderate alcohol consumption might protect the heart “deserves closer attention in future investigations.”

However, Giovanni de Gaetano, MD, PhD, department of epidemiology and prevention, IRCCS NEUROMED, Pozzilli, Italy, one of the authors, emphasized that individuals who consume alcohol should not “exceed the recommended daily dose limits suggested in many countries and that no abstainer should start to drink, even in moderation, solely for the purpose of improving his/her health outcomes.”

Dr. Tawakol and colleagues said that, given alcohol’s adverse health effects, such as heightened cancer risk, new interventions that have positive effects on the neurobiology of stress but without the harmful effects of alcohol are needed.

To that end, they are studying the effect of exercise, stress-reduction interventions such as meditation, and pharmacologic therapies on stress-associated neural networks, and how they might induce CV benefits.

Dr. Tawakol said in an interview that one “additional important message is that anxiety and other related conditions like depression have really substantial health consequences, including increased MACE. Safer interventions that reduce anxiety may yet prove to reduce the risk of heart disease very nicely.”

The study was supported by the National Institutes of Health. Dr. Tawakol and Dr. de Gaetano have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

There was a time when I would have had to explain to you what an N95 mask is, how it is designed to filter out 95% of fine particles, defined as stuff in the air less than 2.5 microns in size.

But of course, you know that now. The N95 had its moment – a moment that seemed to be passing as the concentration of airborne coronavirus particles decreased.

Wikimedia Commons

JAMA Network Open

JAMA Network Open

JAMA Network Open

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. He reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

There was a time when I would have had to explain to you what an N95 mask is, how it is designed to filter out 95% of fine particles, defined as stuff in the air less than 2.5 microns in size.

But of course, you know that now. The N95 had its moment – a moment that seemed to be passing as the concentration of airborne coronavirus particles decreased.

Wikimedia Commons

JAMA Network Open

JAMA Network Open

JAMA Network Open

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. He reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

There was a time when I would have had to explain to you what an N95 mask is, how it is designed to filter out 95% of fine particles, defined as stuff in the air less than 2.5 microns in size.

But of course, you know that now. The N95 had its moment – a moment that seemed to be passing as the concentration of airborne coronavirus particles decreased.

Wikimedia Commons

JAMA Network Open

JAMA Network Open

JAMA Network Open

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. He reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

Insurance companies are starting to send warning letters to doctors and health care providers suspected of off-label prescribing for the drug Ozempic. 

The warning letters, first reported by The Washington Post, include threats such as the possibility of reporting “suspected inappropriate or fraudulent activity ... to the state licensure board, federal and/or state law enforcement.”

It’s the latest chapter in the story of the popular, highly effective, and very expensive drug intended for diabetes that results in quick weight loss. Off-label prescribing means a medicine has been prescribed for a reason other than the uses approved by the Food and Drug Administration.  The practice is common and legal (the U.S. Agency for Healthcare Research and Quality says one in five prescriptions in the U.S. are off label). 

But insurance companies are pushing back because many do not cover weight loss medications, while they do cover diabetes treatments. The insurance company letters suggest that prescribers are failing to document in a person’s medical record that the person actually has diabetes. 

Ozempic, which is FDA approved for treatment of diabetes, is similar to the drug Wegovy, which is approved to be used for weight loss. Ozempic typically costs more than $900 per month. Both Wegovy and Ozempic contain semaglutide, which mimics a hormone that helps the brain regulate appetite and food intake. Clinical studies show that after taking semaglutide for more than 5 years, people lose on average 17% of their body weight. But once they stop taking it, most people regain much of the weight. 

Demand for both Ozempic and Wegovy has been surging, leading to shortages and tactics to acquire the drugs outside of the United States, as well as warnings from public health officials about the dangers of knockoff versions of the drugs. The Centers for Disease Control and Prevention says 42% of people in the United States are obese.

“Obesity is a complex disease involving an excessive amount of body fat,” the Mayo Clinic explained. “Obesity isn’t just a cosmetic concern. It’s a medical problem that increases the risk of other diseases and health problems, such as heart disease, diabetes, high blood pressure, and certain cancers.”

A version of this article first appeared on WebMD.com.

Insurance companies are starting to send warning letters to doctors and health care providers suspected of off-label prescribing for the drug Ozempic. 

The warning letters, first reported by The Washington Post, include threats such as the possibility of reporting “suspected inappropriate or fraudulent activity ... to the state licensure board, federal and/or state law enforcement.”

It’s the latest chapter in the story of the popular, highly effective, and very expensive drug intended for diabetes that results in quick weight loss. Off-label prescribing means a medicine has been prescribed for a reason other than the uses approved by the Food and Drug Administration.  The practice is common and legal (the U.S. Agency for Healthcare Research and Quality says one in five prescriptions in the U.S. are off label). 

But insurance companies are pushing back because many do not cover weight loss medications, while they do cover diabetes treatments. The insurance company letters suggest that prescribers are failing to document in a person’s medical record that the person actually has diabetes. 

Ozempic, which is FDA approved for treatment of diabetes, is similar to the drug Wegovy, which is approved to be used for weight loss. Ozempic typically costs more than $900 per month. Both Wegovy and Ozempic contain semaglutide, which mimics a hormone that helps the brain regulate appetite and food intake. Clinical studies show that after taking semaglutide for more than 5 years, people lose on average 17% of their body weight. But once they stop taking it, most people regain much of the weight. 

Demand for both Ozempic and Wegovy has been surging, leading to shortages and tactics to acquire the drugs outside of the United States, as well as warnings from public health officials about the dangers of knockoff versions of the drugs. The Centers for Disease Control and Prevention says 42% of people in the United States are obese.

“Obesity is a complex disease involving an excessive amount of body fat,” the Mayo Clinic explained. “Obesity isn’t just a cosmetic concern. It’s a medical problem that increases the risk of other diseases and health problems, such as heart disease, diabetes, high blood pressure, and certain cancers.”

A version of this article first appeared on WebMD.com.

Insurance companies are starting to send warning letters to doctors and health care providers suspected of off-label prescribing for the drug Ozempic. 

The warning letters, first reported by The Washington Post, include threats such as the possibility of reporting “suspected inappropriate or fraudulent activity ... to the state licensure board, federal and/or state law enforcement.”

It’s the latest chapter in the story of the popular, highly effective, and very expensive drug intended for diabetes that results in quick weight loss. Off-label prescribing means a medicine has been prescribed for a reason other than the uses approved by the Food and Drug Administration.  The practice is common and legal (the U.S. Agency for Healthcare Research and Quality says one in five prescriptions in the U.S. are off label). 

But insurance companies are pushing back because many do not cover weight loss medications, while they do cover diabetes treatments. The insurance company letters suggest that prescribers are failing to document in a person’s medical record that the person actually has diabetes. 

Ozempic, which is FDA approved for treatment of diabetes, is similar to the drug Wegovy, which is approved to be used for weight loss. Ozempic typically costs more than $900 per month. Both Wegovy and Ozempic contain semaglutide, which mimics a hormone that helps the brain regulate appetite and food intake. Clinical studies show that after taking semaglutide for more than 5 years, people lose on average 17% of their body weight. But once they stop taking it, most people regain much of the weight. 

Demand for both Ozempic and Wegovy has been surging, leading to shortages and tactics to acquire the drugs outside of the United States, as well as warnings from public health officials about the dangers of knockoff versions of the drugs. The Centers for Disease Control and Prevention says 42% of people in the United States are obese.

“Obesity is a complex disease involving an excessive amount of body fat,” the Mayo Clinic explained. “Obesity isn’t just a cosmetic concern. It’s a medical problem that increases the risk of other diseases and health problems, such as heart disease, diabetes, high blood pressure, and certain cancers.”

A version of this article first appeared on WebMD.com.

Johnna Mendenall had never been “the skinny friend,” she said, but the demands of motherhood – along with a sedentary desk job – made weight management even more difficult. Worried that family type 2 diabetes would catch up with her, she decided to start Wegovy shots for weight loss.

She was nervous about potential side effects. It took 5 days of staring at the Wegovy pen before she worked up the nerve for her first .25-milligram shot. And sure enough, the side effects came on strong.

“The nausea kicked in,” she said. “When I increased my dose to 1 milligram, I spent the entire night from 10 p.m. to 5 a.m. vomiting. I almost quit that day.”

Ms. Mendenall is among a growing number of people sharing personal stories online about the weight loss medication Wegovy – and similar drugs – delving into their sometimes unpleasant, and potentially gut-wrenching, side effects. 

While gastrointestinal (GI) symptoms seem to be the most common, a laundry list of others has been discussed in the news, on TikTok, and across online forums. Those include “Ozempic face,” or the gaunt look some get after taking the medication, along with hair loss, anxiety, depression, and debilitating fatigue. 

Ms. Mendenall’s primary side effects have been vomiting, fatigue, and severe constipation, but she has also seen some positive changes: The “food noise,” or the urge to eat when she isn’t hungry, is gone. Since her first dose 12 weeks ago, she has gone from 236 pounds to 215. 
 

Warning label

Wegovy’s active ingredient, semaglutide, mimics the role of a natural hormone called glucagonlike peptide–1 (GLP-1), which helps you feel well fed. Semaglutide is used at a lower dose under the brand name Ozempic, which is approved for type 2 diabetes and used off-label for weight loss.  

Both Ozempic and Wegovy come with a warning label for potential side effects, the most common ones being nausea, diarrhea, stomach pain, and vomiting.

With the surging popularity of semaglutide, more people are getting prescriptions through telemedicine companies, forgoing more in-depth consultations, leading to more side effects, said Caroline Apovian, MD, professor of medicine at Harvard Medical School and codirector of the Center for Weight Management and Wellness at Brigham and Women’s Hospital, Boston.

Specialists say starting with low doses and gradually increasing over time helps avoid side effects, but insurance companies often require a faster timeline to continue covering the medication, Dr. Apovian said. 

“Insurance companies are practicing medicine for us by demanding the patient go up in dosage [too quickly],” she explained. 

Ms. Mendenall’s insurance has paid for her Wegovy shots, but without that coverage, she said it would cost her $1,200 per month. 

There are similar medications on the market, such as liraglutide, sold under the name Saxenda. But it is a daily, rather than a weekly, shot and also comes with side effects and has been shown to be less effective. In one clinical trial, the people being studied saw their average body weight over 68 weeks drop by 15.8% with semaglutide, and by 6.4% with liraglutide.

Tirzepatide, branded Mounjaro – a type 2 diabetes drug made by Eli Lilly that may soon gain Food and Drug Administration approval for weight loss – could have fewer side effects. In clinical trials, 44% of those taking semaglutide had nausea and 31% reported diarrhea, compared with 33% and 23% of those taking tirzepatide, although no trial has directly compared the two agents. 
 

Loss of bowel control 

For now, Wegovy and Saxenda are the only GLP-1 agonist shots authorized for weight loss, and their maker, Danish drug company Novo Nordisk, is facing its second shortage of Wegovy amid growing demand. 

Personal stories online about semaglutide range from overwhelmingly positive – just what some need to win a lifelong battle with obesity – to harsh scenarios with potentially long-term health consequences, and everything in between. 

One private community on Reddit is dedicated to a particularly unpleasant side effect: loss of bowel control while sleeping. Others have reported uncontrollable vomiting.

Kimberly Carew of Clearwater, Fla., started on .5 milligrams of Ozempic last year after her rheumatologist and endocrinologist suggested it to treat her type 2 diabetes. She was told it came with the bonus of weight loss, which she was hoping would help with her joint and back pain. 

But after she increased the dose to 1 milligram, her GI symptoms, which started out mild, became unbearable. She couldn’t keep food down, and when she vomited, the food would often come up whole, she said. 

“One night I ate ramen before bed. And the next morning, it came out just as it went down,” said Ms. Carew, 42, a registered mental health counseling intern. “I was getting severe heartburn and could not take a couple bites of food without getting nauseous.”

She also had “sulfur burps,” a side effect discussed by some Ozempic users, causing her to taste rotten egg sometimes.

She was diagnosed with gastroparesis. Some types of gastroparesis can be resolved by discontinuing GLP-1 medications, as referenced in two case reports in the Journal of Investigative Medicine. 
 

Gut hormone

GI symptoms are most common with semaglutide because the hormone it imitates, GLP-1, is secreted by cells in the stomach, small intestines, and pancreas, said Anne Peters, MD, director of the USC Clinical Diabetes Programs.

“This is the deal: The side effects are real because it’s a gut hormone. It’s increasing the level of something your body already has,” she said. 

But, like Dr. Apovian, Dr. Peters said those side effects can likely be avoided if shots are started at the lowest doses and gradually adjusted up. 

While the average starting dose is .25 milligrams, Dr. Peters said she often starts her patients on about an eighth of that – just “a whiff of a dose.” 

“It’ll take them months to get up to the starting dose, but what’s the rush?” 

Dr. Peters said she also avoids giving diabetes patients the maximum dose, which is 2 milligrams per week for Ozempic (and 2.4 milligrams for Wegovy for weight loss). 

When asked about the drugs’ side effects, Novo Nordisk responded that “GLP-1 receptor agonists are a well-established class of medicines, which have demonstrated long-term safety in clinical trials. The most common adverse reactions, as with all GLP-1 [agonists], are gastrointestinal related.”
 

Is it the drug or the weight loss?

Still, non-gastrointestinal side effects such as hair loss, mood changes, and sunken facial features are reported among semaglutide users across the Internet. While these cases are often anecdotal, they can be very heartfelt.

Celina Horvath Myers, also known as CelinaSpookyBoo, a Canadian YouTuber who took Ozempic for type 2 diabetes, said she began having intense panic attacks and depression after starting the medication. 

“Who I have been these last couple weeks, has probably been the scariest time of my life,” she said on her YouTube channel. 

While severe depression and anxiety are not established side effects of the medication, some people get anhedonia, said W. Scott Butsch, MD, MSc, director of obesity medicine in the Bariatric and Metabolic Institute at Cleveland Clinic. But that could be a natural consequence of lower appetite, he said, given that food gives most people pleasure in the moment.

Many other reported changes come from the weight loss itself, not the medication, said Dr. Butsch.

“These are drugs that change the body’s weight regulatory system,” he said. “When someone loses weight, you get the shrinking of the fat cells, as well as the atrophy of the muscles. This rapid weight loss may give the appearance of one’s face changing.”

For some people, like Ms. Mendenall, the side effects are worth it. For others, like Ms. Carew, they’re intolerable. 

Ms. Carew said she stopped the medication after about 7 months, and gradually worked up to eating solid foods again. 

“It’s the American way, we’ve all got to be thin and beautiful,” she said. “But I feel like it’s very unsafe because we just don’t know how seriously our bodies will react to these things in the long term. People see it as a quick fix, but it comes with risks.”

A version of this article first appeared on WebMD.com.

Johnna Mendenall had never been “the skinny friend,” she said, but the demands of motherhood – along with a sedentary desk job – made weight management even more difficult. Worried that family type 2 diabetes would catch up with her, she decided to start Wegovy shots for weight loss.

She was nervous about potential side effects. It took 5 days of staring at the Wegovy pen before she worked up the nerve for her first .25-milligram shot. And sure enough, the side effects came on strong.

“The nausea kicked in,” she said. “When I increased my dose to 1 milligram, I spent the entire night from 10 p.m. to 5 a.m. vomiting. I almost quit that day.”

Ms. Mendenall is among a growing number of people sharing personal stories online about the weight loss medication Wegovy – and similar drugs – delving into their sometimes unpleasant, and potentially gut-wrenching, side effects. 

While gastrointestinal (GI) symptoms seem to be the most common, a laundry list of others has been discussed in the news, on TikTok, and across online forums. Those include “Ozempic face,” or the gaunt look some get after taking the medication, along with hair loss, anxiety, depression, and debilitating fatigue. 

Ms. Mendenall’s primary side effects have been vomiting, fatigue, and severe constipation, but she has also seen some positive changes: The “food noise,” or the urge to eat when she isn’t hungry, is gone. Since her first dose 12 weeks ago, she has gone from 236 pounds to 215. 
 

Warning label

Wegovy’s active ingredient, semaglutide, mimics the role of a natural hormone called glucagonlike peptide–1 (GLP-1), which helps you feel well fed. Semaglutide is used at a lower dose under the brand name Ozempic, which is approved for type 2 diabetes and used off-label for weight loss.  

Both Ozempic and Wegovy come with a warning label for potential side effects, the most common ones being nausea, diarrhea, stomach pain, and vomiting.

With the surging popularity of semaglutide, more people are getting prescriptions through telemedicine companies, forgoing more in-depth consultations, leading to more side effects, said Caroline Apovian, MD, professor of medicine at Harvard Medical School and codirector of the Center for Weight Management and Wellness at Brigham and Women’s Hospital, Boston.

Specialists say starting with low doses and gradually increasing over time helps avoid side effects, but insurance companies often require a faster timeline to continue covering the medication, Dr. Apovian said. 

“Insurance companies are practicing medicine for us by demanding the patient go up in dosage [too quickly],” she explained. 

Ms. Mendenall’s insurance has paid for her Wegovy shots, but without that coverage, she said it would cost her $1,200 per month. 

There are similar medications on the market, such as liraglutide, sold under the name Saxenda. But it is a daily, rather than a weekly, shot and also comes with side effects and has been shown to be less effective. In one clinical trial, the people being studied saw their average body weight over 68 weeks drop by 15.8% with semaglutide, and by 6.4% with liraglutide.

Tirzepatide, branded Mounjaro – a type 2 diabetes drug made by Eli Lilly that may soon gain Food and Drug Administration approval for weight loss – could have fewer side effects. In clinical trials, 44% of those taking semaglutide had nausea and 31% reported diarrhea, compared with 33% and 23% of those taking tirzepatide, although no trial has directly compared the two agents. 
 

Loss of bowel control 

For now, Wegovy and Saxenda are the only GLP-1 agonist shots authorized for weight loss, and their maker, Danish drug company Novo Nordisk, is facing its second shortage of Wegovy amid growing demand. 

Personal stories online about semaglutide range from overwhelmingly positive – just what some need to win a lifelong battle with obesity – to harsh scenarios with potentially long-term health consequences, and everything in between. 

One private community on Reddit is dedicated to a particularly unpleasant side effect: loss of bowel control while sleeping. Others have reported uncontrollable vomiting.

Kimberly Carew of Clearwater, Fla., started on .5 milligrams of Ozempic last year after her rheumatologist and endocrinologist suggested it to treat her type 2 diabetes. She was told it came with the bonus of weight loss, which she was hoping would help with her joint and back pain. 

But after she increased the dose to 1 milligram, her GI symptoms, which started out mild, became unbearable. She couldn’t keep food down, and when she vomited, the food would often come up whole, she said. 

“One night I ate ramen before bed. And the next morning, it came out just as it went down,” said Ms. Carew, 42, a registered mental health counseling intern. “I was getting severe heartburn and could not take a couple bites of food without getting nauseous.”

She also had “sulfur burps,” a side effect discussed by some Ozempic users, causing her to taste rotten egg sometimes.

She was diagnosed with gastroparesis. Some types of gastroparesis can be resolved by discontinuing GLP-1 medications, as referenced in two case reports in the Journal of Investigative Medicine. 
 

Gut hormone

GI symptoms are most common with semaglutide because the hormone it imitates, GLP-1, is secreted by cells in the stomach, small intestines, and pancreas, said Anne Peters, MD, director of the USC Clinical Diabetes Programs.

“This is the deal: The side effects are real because it’s a gut hormone. It’s increasing the level of something your body already has,” she said. 

But, like Dr. Apovian, Dr. Peters said those side effects can likely be avoided if shots are started at the lowest doses and gradually adjusted up. 

While the average starting dose is .25 milligrams, Dr. Peters said she often starts her patients on about an eighth of that – just “a whiff of a dose.” 

“It’ll take them months to get up to the starting dose, but what’s the rush?” 

Dr. Peters said she also avoids giving diabetes patients the maximum dose, which is 2 milligrams per week for Ozempic (and 2.4 milligrams for Wegovy for weight loss). 

When asked about the drugs’ side effects, Novo Nordisk responded that “GLP-1 receptor agonists are a well-established class of medicines, which have demonstrated long-term safety in clinical trials. The most common adverse reactions, as with all GLP-1 [agonists], are gastrointestinal related.”
 

Is it the drug or the weight loss?

Still, non-gastrointestinal side effects such as hair loss, mood changes, and sunken facial features are reported among semaglutide users across the Internet. While these cases are often anecdotal, they can be very heartfelt.

Celina Horvath Myers, also known as CelinaSpookyBoo, a Canadian YouTuber who took Ozempic for type 2 diabetes, said she began having intense panic attacks and depression after starting the medication. 

“Who I have been these last couple weeks, has probably been the scariest time of my life,” she said on her YouTube channel. 

While severe depression and anxiety are not established side effects of the medication, some people get anhedonia, said W. Scott Butsch, MD, MSc, director of obesity medicine in the Bariatric and Metabolic Institute at Cleveland Clinic. But that could be a natural consequence of lower appetite, he said, given that food gives most people pleasure in the moment.

Many other reported changes come from the weight loss itself, not the medication, said Dr. Butsch.

“These are drugs that change the body’s weight regulatory system,” he said. “When someone loses weight, you get the shrinking of the fat cells, as well as the atrophy of the muscles. This rapid weight loss may give the appearance of one’s face changing.”

For some people, like Ms. Mendenall, the side effects are worth it. For others, like Ms. Carew, they’re intolerable. 

Ms. Carew said she stopped the medication after about 7 months, and gradually worked up to eating solid foods again. 

“It’s the American way, we’ve all got to be thin and beautiful,” she said. “But I feel like it’s very unsafe because we just don’t know how seriously our bodies will react to these things in the long term. People see it as a quick fix, but it comes with risks.”

A version of this article first appeared on WebMD.com.

Johnna Mendenall had never been “the skinny friend,” she said, but the demands of motherhood – along with a sedentary desk job – made weight management even more difficult. Worried that family type 2 diabetes would catch up with her, she decided to start Wegovy shots for weight loss.

She was nervous about potential side effects. It took 5 days of staring at the Wegovy pen before she worked up the nerve for her first .25-milligram shot. And sure enough, the side effects came on strong.

“The nausea kicked in,” she said. “When I increased my dose to 1 milligram, I spent the entire night from 10 p.m. to 5 a.m. vomiting. I almost quit that day.”

Ms. Mendenall is among a growing number of people sharing personal stories online about the weight loss medication Wegovy – and similar drugs – delving into their sometimes unpleasant, and potentially gut-wrenching, side effects. 

While gastrointestinal (GI) symptoms seem to be the most common, a laundry list of others has been discussed in the news, on TikTok, and across online forums. Those include “Ozempic face,” or the gaunt look some get after taking the medication, along with hair loss, anxiety, depression, and debilitating fatigue. 

Ms. Mendenall’s primary side effects have been vomiting, fatigue, and severe constipation, but she has also seen some positive changes: The “food noise,” or the urge to eat when she isn’t hungry, is gone. Since her first dose 12 weeks ago, she has gone from 236 pounds to 215. 
 

Warning label

Wegovy’s active ingredient, semaglutide, mimics the role of a natural hormone called glucagonlike peptide–1 (GLP-1), which helps you feel well fed. Semaglutide is used at a lower dose under the brand name Ozempic, which is approved for type 2 diabetes and used off-label for weight loss.  

Both Ozempic and Wegovy come with a warning label for potential side effects, the most common ones being nausea, diarrhea, stomach pain, and vomiting.

With the surging popularity of semaglutide, more people are getting prescriptions through telemedicine companies, forgoing more in-depth consultations, leading to more side effects, said Caroline Apovian, MD, professor of medicine at Harvard Medical School and codirector of the Center for Weight Management and Wellness at Brigham and Women’s Hospital, Boston.

Specialists say starting with low doses and gradually increasing over time helps avoid side effects, but insurance companies often require a faster timeline to continue covering the medication, Dr. Apovian said. 

“Insurance companies are practicing medicine for us by demanding the patient go up in dosage [too quickly],” she explained. 

Ms. Mendenall’s insurance has paid for her Wegovy shots, but without that coverage, she said it would cost her $1,200 per month. 

There are similar medications on the market, such as liraglutide, sold under the name Saxenda. But it is a daily, rather than a weekly, shot and also comes with side effects and has been shown to be less effective. In one clinical trial, the people being studied saw their average body weight over 68 weeks drop by 15.8% with semaglutide, and by 6.4% with liraglutide.

Tirzepatide, branded Mounjaro – a type 2 diabetes drug made by Eli Lilly that may soon gain Food and Drug Administration approval for weight loss – could have fewer side effects. In clinical trials, 44% of those taking semaglutide had nausea and 31% reported diarrhea, compared with 33% and 23% of those taking tirzepatide, although no trial has directly compared the two agents. 
 

Loss of bowel control 

For now, Wegovy and Saxenda are the only GLP-1 agonist shots authorized for weight loss, and their maker, Danish drug company Novo Nordisk, is facing its second shortage of Wegovy amid growing demand. 

Personal stories online about semaglutide range from overwhelmingly positive – just what some need to win a lifelong battle with obesity – to harsh scenarios with potentially long-term health consequences, and everything in between. 

One private community on Reddit is dedicated to a particularly unpleasant side effect: loss of bowel control while sleeping. Others have reported uncontrollable vomiting.

Kimberly Carew of Clearwater, Fla., started on .5 milligrams of Ozempic last year after her rheumatologist and endocrinologist suggested it to treat her type 2 diabetes. She was told it came with the bonus of weight loss, which she was hoping would help with her joint and back pain. 

But after she increased the dose to 1 milligram, her GI symptoms, which started out mild, became unbearable. She couldn’t keep food down, and when she vomited, the food would often come up whole, she said. 

“One night I ate ramen before bed. And the next morning, it came out just as it went down,” said Ms. Carew, 42, a registered mental health counseling intern. “I was getting severe heartburn and could not take a couple bites of food without getting nauseous.”

She also had “sulfur burps,” a side effect discussed by some Ozempic users, causing her to taste rotten egg sometimes.

She was diagnosed with gastroparesis. Some types of gastroparesis can be resolved by discontinuing GLP-1 medications, as referenced in two case reports in the Journal of Investigative Medicine. 
 

Gut hormone

GI symptoms are most common with semaglutide because the hormone it imitates, GLP-1, is secreted by cells in the stomach, small intestines, and pancreas, said Anne Peters, MD, director of the USC Clinical Diabetes Programs.

“This is the deal: The side effects are real because it’s a gut hormone. It’s increasing the level of something your body already has,” she said. 

But, like Dr. Apovian, Dr. Peters said those side effects can likely be avoided if shots are started at the lowest doses and gradually adjusted up. 

While the average starting dose is .25 milligrams, Dr. Peters said she often starts her patients on about an eighth of that – just “a whiff of a dose.” 

“It’ll take them months to get up to the starting dose, but what’s the rush?” 

Dr. Peters said she also avoids giving diabetes patients the maximum dose, which is 2 milligrams per week for Ozempic (and 2.4 milligrams for Wegovy for weight loss). 

When asked about the drugs’ side effects, Novo Nordisk responded that “GLP-1 receptor agonists are a well-established class of medicines, which have demonstrated long-term safety in clinical trials. The most common adverse reactions, as with all GLP-1 [agonists], are gastrointestinal related.”
 

Is it the drug or the weight loss?

Still, non-gastrointestinal side effects such as hair loss, mood changes, and sunken facial features are reported among semaglutide users across the Internet. While these cases are often anecdotal, they can be very heartfelt.

Celina Horvath Myers, also known as CelinaSpookyBoo, a Canadian YouTuber who took Ozempic for type 2 diabetes, said she began having intense panic attacks and depression after starting the medication. 

“Who I have been these last couple weeks, has probably been the scariest time of my life,” she said on her YouTube channel. 

While severe depression and anxiety are not established side effects of the medication, some people get anhedonia, said W. Scott Butsch, MD, MSc, director of obesity medicine in the Bariatric and Metabolic Institute at Cleveland Clinic. But that could be a natural consequence of lower appetite, he said, given that food gives most people pleasure in the moment.

Many other reported changes come from the weight loss itself, not the medication, said Dr. Butsch.

“These are drugs that change the body’s weight regulatory system,” he said. “When someone loses weight, you get the shrinking of the fat cells, as well as the atrophy of the muscles. This rapid weight loss may give the appearance of one’s face changing.”

For some people, like Ms. Mendenall, the side effects are worth it. For others, like Ms. Carew, they’re intolerable. 

Ms. Carew said she stopped the medication after about 7 months, and gradually worked up to eating solid foods again. 

“It’s the American way, we’ve all got to be thin and beautiful,” she said. “But I feel like it’s very unsafe because we just don’t know how seriously our bodies will react to these things in the long term. People see it as a quick fix, but it comes with risks.”

A version of this article first appeared on WebMD.com.